Heteroaromatic compounds and their use as dopamine d1 ligands

ABSTRACT

and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), schizotypal personality disorder, cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, Parkinson&#39;s disease, anxiety, and depression.

This application is a division of U.S. application Ser. No. 15/822,493filed Nov. 27, 2017, which is in turn a continuation of Ser. No.15/305,372 filed Oct. 20, 2016 (issued as U.S. Pat. No. 9,868,744 onJan. 16, 2018), which in turn is a national phase filing under 35 U.S.C.§ 371 of international patent application number PCT/162015/052672 filedApr. 13, 2015, which in turn claims the benefit of priority to U.S.Provisional Patent Application Ser. No. 61/984,086 filed Apr. 25, 2014,the disclosure of each of these applications is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to heteroaromatic compounds,which are dopamine D1 ligands, for example dopamine D1 agonists orpartial agonists.

BACKGROUND OF THE INVENTION

Dopamine acts upon neurons through two families of dopamine receptors,D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D1-likereceptor family consists of D1 and D5 receptors which are expressed inmany regions of the brain. D1 mRNA has been found, for example, in thestriatum and nucleus accumbens. See e.g., Missale C, Nash S R, RobinsonS W, Jaber M, Caron M G “Dopamine receptors: from structure tofunction”, Physiological Reviews 78:189-225 (1998). Pharmacologicalstudies have reported that D1 and D5 receptors (D1/D5), namely D1-likereceptors, are linked to stimulation of adenylyl cyclase, whereas D2,D3, and D4 receptors, namely D2-like receptors, are linked to inhibitionof cAMP production.

Dopamine D1 receptors are implicated in numerous neuropharmacologicaland neurobiological functions. For example, D1 receptors are involved indifferent types of memory function and synaptic plasticity. See e.g.,Goldman-Rakic P S et al., “Targeting the dopamine D1 receptor inschizophrenia: insights for cognitive dysfunction”, Psychopharmacology174(1):3-16 (2004). Moreover, D1 receptors have been implicated in avariety of psychiatric, neurological, neurodevelopmental,neurodegenerative, mood, motivational, metabolic, cardiovascular, renal,ophthalmic, endocrine, and/or other disorders described herein includingschizophrenia (e.g., cognitive and negative symptoms in schizophrenia),schizotypal personality disorder, cognitive impairment associated withD2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mildcognitive impairment (MCI), age-related cognitive decline, Alzheimer'sdementia, Parkinson's disease (PD), Huntington's chorea, depression,anxiety, treatment-resistant depression (TRD), bipolar disorder, chronicapathy, anhedonia, chronic fatigue, post-traumatic stress disorder,seasonal affective disorder, social anxiety disorder, post-partumdepression, serotonin syndrome, substance abuse and drug dependence,Tourette's syndrome, tardive dyskinesia, drowsiness, sexual dysfunction,migraine, systemic lupus erythematosus (SLE), hyperglycemia,dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis,renal failure, resistant edema, narcolepsy, hypertension, congestiveheart failure, postoperative ocular hypotonia, sleep disorders, pain,and other disorders in a mammal. See e.g., Goulet M, Madras B K “D(1)dopamine receptor agonists are more effective in alleviating advancedthan mild parkinsonism in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys”, Journalof Pharmacology and Experimental Therapy 292(2):714-24 (2000); SurmeierD J et al., “The role of dopamine in modulating the structure andfunction of striatal circuits”, Prog. Brain Res. 183:149-67 (2010).

New or improved agents that modulate (such as agonize or partiallyagonize) D1R are needed for developing new and more effectivepharmaceuticals to treat diseases or conditions associated withdysregulated activation of D1R, such as those described herein.

WO2013026516 reports bicyclic heteroaromatic compounds having thefollowing structure

that are kinase inhibitors and can be used, for example, for treatingtumors.

CN102558147 reports pyridinecarboxamide derivatives of the followingformula:

as inhibitors of tyrosine kinase and/or serine-threonine kinase fortreating cancer.

WO2007009524 reports 2-arylbenzothiazoles of the following formula

useful as protein kinase inhibitors for treating diseases such as thoseassociated with abnormal and hyperproliferation of cells.

US2005/0153989 reports compounds of the following structure

useful for treating and/or preventing conditions and diseases associatedwith kinase activity, e. g., EGFR activity, such as cancer, hyperplasia,psoriasis, cardiac hypertrophy, arthrosclerosis, dermatitis and/ordiseases or conditions associated with undesired cellularhyperproliferation.

Abou-Zeid, K. A. M. et al, “synthesis of 6-(4-(substitutedamino)phenyl)-4,5-dihydropyridazin-3(2H)-ones as potential positiveinotropic agents,” Egyptian Journal of Pharmaceutical Sciences (1998),Volume Date 1997, 38(4-6), 319-331, reports some pyridazinones, forexample,

that were evaluated as inhibitors of cardiac cAMP phosphodiesterase.

Demange, L. et. al, “Synthesis and evaluation of new potent inhibitorsof CK1 and CDK5, two kinases involved in Alzheimer's disease,” MedicinalChemistry Research (2013), 22(7), 3247-3258 reports compounds having oneof following structures

as inhibitors of CK1 and CDK5. In addition, it also reports certainintermediates having one of the following structures:

US20100317646 reports pyrazolopyridine compounds of the followingstructure

as kinase inhibitors (e.g., LRRK or LRRK2 inhibitors).

US20100247517 reports compounds having one of the following structures

useful for the production of pharmaceutical compositions for theprophylaxis and/or treatment of diseases which can be influenced by theinhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b)and/or variants thereof.

Bischoff, F. et. al, “Design and Synthesis of a Novel Series of BicyclicHeterocycles As Potent γ-Secretase Modulators,” Journal of MedicinalChemistry (2012), 55(21), 9089-9106 reports ceratain imidazolecontaining compounds γ-secretase modulators including the following twocompounds:

US2012/0022090 reports substituted benzoxazole, benzimidazole,oxazolopyridine, and imidazopyridine derivative of the followingstructure

that are γ-secretase modulators useful in the treatment of diseases.

US2011/0281881 reports substituted bicyclic derivative of the followingstructure

wherein Het² can be

as γ-secretase modulators useful in the treatment of diseases such asAlzheimer's Disease.

WO2008067420 reports compounds of one of the flowing structures

or pharmaceutically acceptable salts, prodrugs, or tautomers thereof, ascaspase activators and inducers of apoptosis.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a method for treatinga D1-mediated (or D1-associated) disorder in a mammal, which methodcomprises administering to said mammal a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is O, S, NO, C(═O), CH(OH), or CH(OCH₃);

Q¹ is an N-containing 5- to 10-membered heteroaryl, an N-containing 4-to 12-membered heterocycloalkyl, or phenyl, each optionally substitutedwith one R⁹ and further optionally substituted with 1, 2, 3, or 4 R¹⁰;

X¹ is O, S, NH, N(C₁₋₄ alkyl), N(cyclopropyl), or N(—CH₂-cyclopropyl);

X² is N or C-T²;

X³ is N or C-T³;

provided that when X¹ is O or S, then at least one of X² and X³ is notN;

X⁴ is N or C-T⁴;

T¹ is H, —OH, halogen, —CN, or optionally substituted C₁₋₂ alkyl;

each of T², T³, and T⁴ is independently selected from the groupconsisting of H, —OH, halogen, —CN, optionally substituted C₁₋₄ alkyl,optionally substituted C₃₋₄ cycloalkyl, optionally substitutedcyclopropylmethyl, and optionally substituted C₁₋₄ alkoxy;

R^(N) is H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, or —C₁₋₂ alkyl-C₃₋₄ cycloalkyl,

each of R¹ and R² is independently selected from the group consisting ofH, halogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, and C₃₋₆ cycloalkyl, wherein each of said C₁₋₆ alkyl andC₃₋₆ cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents each independently selected from halo, —OH, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

each of R³ and R⁴ is independently selected from the group consisting ofH, halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —NO₂, —CN, —SF₅, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R⁵)(R⁶),—N(R⁷)(C(═O)R⁸), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸,—N(R⁷)(S(═O)₂R⁸), —S(═O)₂—N(R⁵)(R⁶), —SR⁸, and —OR⁸, wherein each ofsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and heterocycloalkyl is optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R⁵)(R⁶),—N(R⁷)(C(═O)R⁸), —C(═O)—OR⁸, —C(═O)H, —C(═O)R⁸, —C(═O)N(R⁵)(R⁶),—N(R⁷)(S(═O)₂R⁸), —S(═O)₂ ⁻N(R⁵)(R⁶), —SR⁸, and —OR⁸;

or R¹ and R³ together with the two carbon atoms to which they areattached form a fused N-containing 5- or 6-membered heteroaryl, a fusedN-containing 5- or 6-membered heterocycloalkyl, a fused 5- or 6-memberedcycloalkyl, or a fused benzene ring, each optionally substituted with 1,2, or 3 substituents each independently selected from the groupconsisting of halo, —CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy;

R⁵ is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₇ cycloalkyl;

R⁶ is H or selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, a 4- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-to 10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-,and (5- to 10-membered heteroaryl)-C₁₋₄ alkyl-, wherein each of theselections from the group is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting of—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxylalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy;

or R⁵ and R⁶ together with the N atom to which they are attached form a4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl,each optionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —OH, —NH₂,—NH(CH₃), —N(CH₃)₂, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C₁₋₄ alkyl,—C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄hydroxylalkyl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R⁷ is selected from the group consisting of H, C₁₋₄ alkyl, and C₃₋₇cycloalkyl;

R⁸ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₇ cycloalkyl,a 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, a 5- to 10-memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and (5- to10-membered heteroaryl)-C₁₋₄ alkyl-, wherein each of the selections fromthe group is optionally substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of halogen, —CF₃, —CN,—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, andC₁₋₄ haloalkoxy;

each of R⁹ and R¹⁰ is independently selected from the group consistingof halogen, —OH, —CN, —SF_(S), —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-memberedheterocycloalkyl, a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₄alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀aryl)-C₁₋₄ alkyl-, (5- to 10-membered heteroaryl)-C₁₋₄ alkyl-,—N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸), —S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶),—C(═O)—R⁸, —C(═O)—OR⁸, —SR⁸, and —OR⁸, wherein each of said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4- to 10-membered heterocycloalkyl, 5- to10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and(5- to 10-membered heteroaryl)-C₁₋₄ alkyl- is optionally substitutedwith 1, 2, 3, or 4 substituents each independently selected from thegroup consisting of halogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄hydroxylalkyl, C₁₋₄ alkoxy, —N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄alkyl), C₆₋₁₀ aryloxy, [(C₆₋₁₀ aryl)-C₁₋₄ alkyloxy- optionallysubstituted with 1 or 2 C₁₋₄ alkyl], oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl,—C(═O)O—C₁₋₄ alkyl, —C(═O)NH₂, —NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇cycloalkyl, a 5- or 6-membered heteroaryl, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy;

or R⁹ and an adjacent R¹⁰ together with the two ring atoms on Q¹ towhich they are attached form a fused benzene ring or a fused 5- or6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5independently selectedR^(10a); and

each R^(10a) is independently selected from the group consisting ofhalogen, —OH, —N(R⁵)(R⁶), —C(═O)OH, —C(═O)—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, —CN, —SF₅, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄hydroxylalkyl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy, with the provisosthat

(1) when X⁴ is N and X¹ is NH, N(C₁₋₄ alkyl), N(cyclopropyl),N(—CH₂-cyclopropyl), or S, then L¹ is other than NR^(N);(2) when X¹ is NH then X³ is other than N;(3) when X² is N, X³ is C-T³, X⁴ is C-T⁴, T³ is not H, and X¹ is NH,then L¹ is other than O or NR^(N);(4) when X² is C-T², X³ is C-T³, X⁴ is C-T⁴, then X¹ is other than S orO;(5) when L¹ is O, X³ is C-T³, and X⁴ is C-T⁴, then X¹ is other than NH;(6) when X¹ is NH, N(C₁₋₄ alkyl), N(cyclopropyl), N(—CH₂-cyclopropyl),or O, and X³ is N then L¹ is other than NR^(N); and(7) Q¹ is other than an optionally substituted benzo[d]thiazolyl (e.g.,benzo[d]thiazol-2-yl) or an optionally substituted monocyclic2-oxo-1H-pyridin-1-yl.

In some embodiments, when X⁴ is N, then L¹ is other than NR^(N).

In some embodiments, L¹ is other than NR^(N).

In some embodiments, when X⁴ is N, then X¹ is other than NH, N(C₁₋₄alkyl), N(cyclopropyl), or N(—CH₂-cyclopropyl).

In some embodiments, when X⁴ is N, then X¹ is other than S.

In some embodiments, when X⁴ is N, then X¹ is other than NH, N(C₁₋₄alkyl), N(cyclopropyl), N(—CH₂-cyclopropyl), or S.

In some embodiments, Q¹ is other than an optionally substitutedmonocyclic 2-oxo-1H-pyridin-1-yl.

In some embodiments, when X² is N, X³ is C-T³, and X⁴ is C-T⁴, then X¹is other than NH.

In some embodiments, when X³ is C-T³, and X⁴ is C-T⁴, then X¹ is otherthan NH.

In some embodiments, L¹ is other than NR^(N); Q¹ is other than anoptionally substituted benzo[d]thiazolyl; Q¹ is other than an optionallysubstituted phenyl; when X⁴ is N, then X¹ is other than NH, N(C₁₋₄alkyl), N(cyclopropyl), N(—CH₂-cyclopropyl) or S; and when X³ is C-T³,and X⁴ is C-T⁴, then X¹ is other than NH. In some further embodiments,Q¹ is other than an optionally substituted monocyclic2-oxo-1H-pyridin-1-yl. In some yet further embodiments, L¹ is O or S. Instill further embodiments, L¹ is O.

In some embodiments, the disorder is selected from schizophrenia (e.g.,cognitive and negative symptoms in schizophrenia), schizotypalpersonality disorder, cognitive impairment [e.g., cognitive impairmentassociated with schizophrenia, cognitive impairment associated with AD,cognitive impairment associated with PD, cognitive impairment associatedwith pharmacotherapy therapy (e.g., D2 antagonist therapy)], attentiondeficit hyperactivity disorder (ADHD), impulsivity, compulsive gambling,overeating, autism spectrum disorder, mild cognitive impairment (MCI),age-related cognitive decline, dementia (e.g., senile dementia,HIV-associated dementia, Alzheimer's dementia, Lewy body dementia,vascular dementia, or frontotemporal dementia), restless leg syndrome(RLS), Parkinson's disease, Huntington's chorea, anxiety, depression(e.g., age-related depression), major depressive disorder (MDD),treatment-resistant depression (TRD), bipolar disorder, chronic apathy,anhedonia, chronic fatigue, post-traumatic stress disorder, seasonalaffective disorder, social anxiety disorder, post-partum depression,serotonin syndrome, substance abuse and drug dependence, drug abuserelapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessivedaytime sleepiness, cachexia, inattention, sexual dysfunction (e.g.,erectile dysfunction or post-SSRI sexual dysfunction), migraine,systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis,dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis,renal failure, hyponatremia, resistant edema, narcolepsy, hypertension,congestive heart failure, postoperative ocular hypotonia, sleepdisorders, and pain.

In some embodiments, L¹ is O or S. In some further embodiments, L¹ is S.

In some embodiments, L¹ is O.

In some embodiments, L¹ is NH.

In some embodiments, L¹ is C(═O), CH(OH), or CH(OCH₃). In some furtherembodiments, L¹ is C(═O) or CH(OH).

In some embodiments, T¹ is H, F, CI, methyl, or C₁ fluoroalkyl; and eachof T², T³, and T⁴ is independently selected from the group consisting ofH, halogen, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, C₃₋₄halocycloalkyl, cyclopropylmethyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. Insome further embodiments, each of T², T³, and T⁴ is independentlyselected from the group consisting of H, halogen, —CN, methoxy,fluoroalkoxy, methyl, and C₁ fluoroalkyl,

In some embodiments, T¹ is H, F, Cl, methyl, or C₁ fluoroalkyl.

In some embodiments, T¹ is H and T⁴ is H.

In some embodiments, each of T² and T³ is independently H, CN, F, Cl,Br, methyl, methoxy, C₁ fluoroalkoxy, or C₁ fluoroalkyl.

In some embodiments, X¹ is O.

In some embodiments, X¹ is O; and 0 or 1 of X² and X³ is N. In somefurther embodiments, X⁴ is N.

In some embodiments, X¹ is O; 1 of X² and X³ is N, and X⁴ is C-T⁴.

In some embodiments, X¹ is S.

In some embodiments, X¹ is S; and 0 or 1 of X² and X³ is N. In somefurther embodiments, X⁴ is N.

In some embodiments, X¹ is S; 1 of X² and X³ is N, and X⁴ is C-T⁴.

In some embodiments, X¹ is NH.

In some embodiments, X¹ is NH; and 0 or 1 of X² and X³ is N. In somefurther embodiments, X⁴ is C-T⁴.

In some embodiments, X¹ is NH; X² is C-T²; and X³ is N.

In some embodiments, X⁴ is N; and X¹ is O or S. In some furtherembodiments, 0 or 1 of X² and X³ is N.

In some embodiments, X⁴ is N; and X¹ is O. In some further embodiments,0 or 1 of X² and X³ is N.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-d:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-e:

or a pharmaceutically acceptable salt thereof.

The embodiments described herein in the first aspect of the invention,unless specified otherwisely, include the methods for use of a compoundof Formula I, I-a, I-b, I-c, I-d, or I-e, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, each of R¹ and R² is independently H or halogen.

In some further embodiments, each of R¹ and R² is H.

In some embodiments, each of R³ and R⁴ is independently H, halogen, —CN,methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy.

In some embodiments, R³ is H and R⁴ is H, halogen, —CN, methyl, or C₁haloalkyl.

In some embodiments, R³ is H and R⁴ is methyl.

In some embodiments, Q¹ is an N-containing 5- to 6-membered heteroarylor an N-containing 5- to 6-membered heterocycloalkyl, each optionallysubstituted with one R⁹ and 1, 2, 3, or 4 R¹⁰.

In some embodiments, Q¹ is an N-containing 5- to 6-membered heteroarylor an N-containing 5- to 6-membered heterocycloalkyl, each substitutedwith one R⁹ and further optionally substituted with 1, 2, 3, or 4 R¹⁰.

In some embodiment:

R⁹ is halogen (e.g. Cl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —SF₅,—N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkoxy, or C₃₋₇cycloalkyl, wherein each of the C₁₋₄ alkyl and C₃₋₇ cycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —N(R⁵)(R⁶),C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy;

each R¹⁰ is independently selected from the group consisting of halogen,—OH, —CN, —SF_(S), —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl,a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5-to 10-membered heteroaryl)-C₁₋₄ alkyl-, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, —SR⁸, and—OR⁸, wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4-to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and (5- to 10-memberedheteroaryl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting ofhalogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ hydroxylalkyl, C₁₋₄ alkoxy,—N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄ alkyl), C₆₋₁₀ aryloxy,[(C₆₋₁₀ aryl)-C₁₋₄ alkyloxy-optionally substituted with 1 or 2 C₁₋₄alkyl], oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄ alkyl, —C(═O)NH₂,—NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a 5- or 6-memberedheteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or R⁹ and an adjacent R¹⁰ together with the two ring atoms on Q¹ towhich they are attached form a fused benzene ring or a fused 5- or6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(10a).

In some embodiment, R⁹ is halogen (e.g. Cl), C₁₋₄ alkyl, C₁₋₄ haloalkyl,—CN, —SF₅, —N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkoxy,or C₃₋₇ cycloalkyl, wherein each of the C₁₋₄ alkyl and C₃₋₇ cycloalkylis optionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —N(R⁵)(R⁶),C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy. In some further embodiments, R⁹ is C₁₋₄ alkyl, C₁₋₄haloalkyl, —CN, —SF₅, —N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇cycloalkoxy, or C₃₋₇ cycloalkyl, wherein each of the C₁₋₄ alkyl and C₃₋₇cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituentseach independently selected from the group consisting of halogen,—N(R⁵)(R⁶), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy.

In some embodiments:

Q¹ is a moiety of

ring Q^(1a) is an N-containing 5- to 6-membered heteroaryl or anN-containing 5- to 6-membered heterocycloalkyl;

represents a single bond or double bond;

each of Z¹ and Z² is independently C or N;

R⁹ is halogen (e.g. Cl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl,—CN, —N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or C₃₋₇ cycloalkoxy,wherein each of the C₁₋₄ alkyl and C₃₋₇ cycloalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents each independentlyselected from the group consisting of halogen, —N(R⁵)(R⁶), C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

each R¹⁰ is independently selected from the group consisting of halogen,—OH, —CN, —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl,a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5-to 10-membered heteroaryl)-C₁₋₄ alkyl-, (5- to 10-memberedheteroaryl)-C₂₋₄ alkenyl-, —N(R⁵)(R⁶), N(R⁷)(C(═O)R⁸), —S(═O)₂N(R⁵)(R⁶),—C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, and —OR⁸, wherein each of saidC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4- to 10-memberedheterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀aryl)-C₁₋₄ alkyl-, (5- to 10-membered heteroaryl)-C₁₋₄ alkyl-, and (5-to 10-membered heteroaryl)-C₂₋₄ alkenyl- is optionally substituted with1, 2, 3, or 4 substituents each independently selected from the groupconsisting of halogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ hydroxylalkyl,C₁₋₄ alkoxy, —N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄ alkyl), C₆₋₁₀aryloxy, (C₆₋₁₀ aryl)-C₁₋₄ alkyloxy-optionally substituted with 1 or 2C₁₋₄ alkyl, oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄ alkyl,—C(═O)NH₂, —NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a 5- or6-membered heteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or R⁹ and the adjacent R¹⁰ together with the two ring atoms on ringQ^(1a) to which they are attached form a fused benzene ring or a fused5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3,4, or 5 independently selected R^(10a);

each R^(10a) is independently selected from the group consisting ofhalogen, —OH, —C(═O)OH, —C(═O)—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ hydroxylalkyl, (C₁₋₂alkoxy)-C₁₋₄ alkyl-, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and

m is 0, 1, 2, 3, or 4.

In some embodiments, Q¹ is a moiety of Moiety M¹ and Z¹ is C.

In some embodiments, Q¹ or ring Q^(1a) is an optionally substitutedN-containing 6-membered heteroaryl.

In some embodiments, Q¹ or ring Q^(1a) is an optionally substitutedpyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some furtherembodiments, Q¹ or ring Q^(1a) is an optionally substituted pyrimidinyl,pyridazinyl, or pyrazinyl.

In some embodiments, Q¹ or ring Q^(1a) is pyrimidinyl, pyridazinyl, orpyrazinyl, each of which is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting ofOH, halogen (e.g., Cl), CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂alkoxy)-C₁₋₄ alkyl-, and C₃₋₇ cycloalkyl. In some further embodiments,Q¹ or ring Q^(1a) is pyrimidinyl, pyridazinyl, or pyrazinyl, each ofwhich is optionally substituted with 1, 2, 3, or 4 substituents eachindependently selected from the group consisting of CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, and C₃₋₇ cycloalkyl. In stillfurther embodiments, Q¹ or ring Q^(1a) is pyrimidinyl, pyridazinyl, orpyrazinyl, each of which is optionally substituted with 1 or 2substituents each independently selected from the group consisting ofCN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In some embodiments, Moiety M¹ is selected from the group consisting ofquinolinyl, isoquinolinyl, 1H-imidazo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl,imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl,9H-purinyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[1,5-a]pyrimidinyl, isoxazolo[5,4-c]pyridazinyl,isoxazolo[3,4-c]pyridazinyl, and [1,2,4]triazolo[4,3-b]pyridazinyl, eachoptionally substituted with 1, 2, or 3 R¹⁰ and further optionallysubstituted with 1 or 2 R^(10a); or wherein Moiety M¹ is selected fromthe group consisting of pyrimidinyl, pyrazinyl, pyridinyl, pyridazinyl,1H-pyrazolyl, 1H-pyrrolyl, 4H-pyrazolyl, 1H-imidazolyl, 1H-imidazolyl,3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl,2,4(1H,3H)-dioxo-pyrimidinyl, and 1H-2-oxo-pyrazinyl, each substitutedwith R⁹ and further optionally substituted with 1, 2, or 3 R¹⁰.

In some embodiments:

Moiety M¹ is

R^(10a) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, orC₃₋₇ cycloalkyl;

t1 is 0 or 1; and

t is 0 or 1.

In some embodiments, Moiety M¹ is

In some embodiments, Moiety M¹ is

In some embodiments:

Moiety M¹ is

and

R¹¹ is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, or C₃₋₇cycloalkyl.

In some embodiments, R⁹ is halogen (e.g., Cl), C₃₋₆ cycloalkyl (e.g.,cyclopropyl), C₁₋₄ alkyl, or —CN. In some further embodiments, R⁹ ishalogen (e.g., Cl), C₁₋₄ alkyl, or —CN.

In some embodiments, R⁹ is C₁₋₄ alkyl or —CN. In some furtherembodiments, R⁹ is C₁₋₄ alkyl. In some yet further embodiments, R⁹ ismethyl.

In some embodiments, each R¹⁰ is independently selected from the groupconsisting of halogen (e.g., Cl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂alkoxy)-C₁₋₄ alkyl-, —CN, and —N(R⁵)(R⁶), wherein each of R⁵ and R⁶independently is H or selected from the group consisting of C₁₋₄ alkyl,C₁₋₄ haloalkyl, and C₃₋₇ cycloalkyl; or R⁵ and R⁶ together with the Natom to which they are attached form a 4- to 7-membered heterocycloalkylor a 5-membered heteroaryl, each optionally substituted with 1, 2, or 3substituents each independently selected from the group consisting ofhalogen, —CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy. In some further embodiments, each R¹⁰ isindependently halogen (e.g., Cl), C₁₋₄ alkyl or CN. In yet furtherembodiments, each R¹⁰ is independently C₁₋₄ alkyl or CN. In still yetfurther embodiments, each R¹⁰ is C₁₋₄ alkyl (e.g., methyl). In furtherembodiments, each R¹⁰ is C₁₋₄ alkyl methyl.

In some embodiments, each of R⁹ and R¹⁰ is independently halogen (e.g.,Cl), C₃₋₆ cycloalkyl (e.g., cyclopropyl), C₁₋₄ alkyl, or —CN. In somefurther embodiments, each of R⁹ and R¹⁰ is independently halogen (e.g.,Cl), C₁₋₄ alkyl, or —CN.

In some embodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl orCN. In some further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; X⁴ is N; Q¹ is M¹; and M¹ is as described inone of the embodiments provided herein (e.g., M¹-g, M¹-k, M¹-m, orM¹-n). In some further embodiments, L¹ is O or S. In yet furtherembodiments, L¹ is O. In still further embodiments, each of R¹ and R² isindependently H or halogen; and each of R³ and R⁴ is independently H,halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yetstill further embodiments, each of R¹ and R² is H; R³ is H; and R⁴ ismethyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is as described in one of theembodiments provided herein (e.g.; M¹-g, M¹-k, M¹-m, or M¹-n). In somefurther embodiments, L¹ is O or S. In yet further embodiments, L¹ is O.In still further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is N, X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; X⁴ is N; Q¹ is M¹; and M¹ is as described inone of the embodiments provided herein (e.g., M¹-k, M¹-m, or M¹-n). Insome further embodiments, L¹ is O or S. In yet further embodiments, L¹is O. In still further embodiments, each of R¹ and R² is independently Hor halogen; and each of R³ and R⁴ is independently H, halogen, —CN,methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, orhaloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is as described in one of theembodiments provided herein (e.g. M¹-g, M¹-k, M¹-m, or M¹-n). In somefurther embodiments, L¹ is O or S. In yet further embodiments, L¹ is O.In still further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is N, X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is as described in oneof the embodiments provided herein (e.g., M¹-k, M¹-m, or M¹-n). In somefurther embodiments, L¹ is O or S. In yet further embodiments, L¹ is O.In still further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

The first aspect of the invention includes any subset of any embodimentdescribed herein.

The first aspect of the invention includes combinations of two or moreembodiments described herein, or any subset thereof.

The first aspect of the invention further provides the compound ofFormula I or a pharmaceutically acceptable salt thereof (including allembodiments and combinations of two or more embodiments described hereinor any subset thereof) for use in treating a D1-mediated (orD1-associated) disorder described herein.

The first aspect of the invention further provides use of the compoundof Formula I or a pharmaceutically acceptable salt thereof (includingall embodiments and combinations of two or more embodiments describedherein or any subset thereof) for treating a D1-mediated (orD1-associated) disorder described herein.

The first aspect of the invention further provides use of the compoundof Formula I or a pharmaceutically acceptable salt thereof (includingall embodiments and combinations of two or more embodiments describedherein or any subset thereof) in manufacturing a medicament for use intreating a D1-mediated (or D1-associated) disorder described herein.

The term “therapeutically effective amount” as used herein refers tothat amount of the compound (including a pharmaceutically acceptablesalt thereof) being administered which will relieve to some extent oneor more of the symptoms of the disorder being treated. In reference tothe treatment of a D1-mediated disorder (e.g., schizophrenia), atherapeutically effective amount refers to that amount which has theeffect of relieving to some extent (or, for example, eliminating) one ormore symptoms associated with a D1-mediated disorder (e.g.,schizophrenia, or cognitive and negative symptoms in schizophrenia, orcognitive impairment associated with schizophrenia).

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined herein. The term “treating” also includes adjuvantand neo-adjuvant treatment of a subject.

The compound of Formula I or its salt used in the method for treating aD1-mediated (or D1-associated) disorder of present invention is a D1Rmodulator (e.g., a D1 agonist for example, a D1 partial agonist). Theamount of the compound of Formula I or a pharmaceutically acceptableamount used in the method of the present invention is effective inmodulating (e.g., agonizing or partially agonizing) D1 R.

The present invention further provides a method for modulating (such asagonizing or partially agonizing) an activity of D1R (either in vitro orin vivo), comprising contacting (including incubating) the D1R with acompound of Formula I or a pharmaceutically acceptable salt thereof(such as one selected from Examples 1-23 herein) described herein.

In a second aspect, the present invention provides a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is O, S, NR^(N), C(═O), or CH(OH);

Q¹ is an N-containing 5- to 6-membered heteroaryl or an N-containing 5-to 6-membered heterocycloalkyl, each optionally substituted with one R⁹and further optionally substituted with 1, 2, 3, or 4 R¹⁰;

X¹ is O, S, or NH;

X² is N or C-T²;

X³ is N or C-T³;

provided that when X¹ is O or S, then at least one of X² and X² is notN;

X⁴ is N or C-T⁴;

T¹ is H, F, CI, methyl, or C₁ fluoroalkyl;

each of T², T³, and T⁴ is independently selected from the groupconsisting of H, halogen, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄cycloalkyl, C₃₋₄ halocycloalkyl, cyclopropylmethyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy;

R^(N) is H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, or —C₁₋₂ alkyl-C₃₋₄ cycloalkyl,

each of R¹ and R² is independently selected from the group consisting ofH, halogen, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₃₋₆ cycloalkyl, —C(═O)OH, and C(═O)—O—(C₁₋₄ alkyl), whereineach of said C₁₋₆ alkyl and C₃₋₆ cycloalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents each independently selected fromhalo, —OH, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy;

each of R³ and R⁴ is independently selected from the group consisting ofH, halogen, —OH, —NO₂, —CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, a 4- to10-membered heterocycloalkyl, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, —OC(═O)R⁸, —N(R⁷)(S(═O)₂R⁸),—S(═O)₂—N(R⁵)(R⁶), —SR⁸, and —OR⁸, wherein each of said C₁₋₆ alkyl, C₃₋₇cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or3 substituents each independently selected from the group consisting ofhalogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸), —C(═O)—OR⁸,—C(═O)H, —C(═O)R⁸, —C(═O)N(R⁵)(R⁶), —N(R⁷)(S(═O)₂R⁸), —S(═O)₂—N(R⁵)(R⁶),—SR⁸, and −OR⁸;

or R¹ and R³ together with the two carbon atoms to which they areattached form a fused N-containing 5- or 6-membered heteroaryl, a fusedN-containing 5- or 6-membered heterocycloalkyl, a fused 5- or 6-memberedcycloalkyl, or a fused benzene ring, each optionally substituted with 1,2, or 3 substituents each independently selected from the groupconsisting of halo, —CN, —OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,and C₁₋₃ haloalkoxy;

R⁵ is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₃₋₇ cycloalkyl;

R⁶ is H or selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, a 4- to 10-membered heterocycloalkyl, C₆₋₁₀aryl, a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-to 10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-,and (5- to 10-membered heteroaryl)-C₁₋₄ alkyl-, wherein each of theselections from the group is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting of—OH, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxylalkyl, —S—C₁₋₄alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

or R⁵ and R⁶ together with the N atom to which they are attached form a4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl,each optionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —OH, oxo,—C(═O)H, —C(═O)OH, —C(═O)—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂,—CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ hydroxylalkyl, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

R⁷ is selected from the group consisting of H, C₁₋₄ alkyl, and C₃₋₇cycloalkyl;

R⁸ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₇ cycloalkyl,a 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, a 5- to 10-memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and (5- to10-membered heteroaryl)-C₁₋₄ alkyl-, wherein each of the selections fromthe group is optionally substituted with 1, 2, or 3 substituents eachindependently selected from the group consisting of halogen, —CF₃, —CN,—OH, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

R⁹ is halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —SF₅, —N(R⁵)(R⁶), C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkoxy, or C₃₋₇ cycloalkyl, whereineach of the C₁₋₄ alkyl and C₃₋₇ cycloalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents each independently selected from thegroup consisting of halogen, —N(R⁵)(R⁶), C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

each R¹⁰ is independently selected from the group consisting of halogen,—OH, —CN, —SF₅, —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl,a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5-to 10-membered heteroaryl)-C₁₋₄ alkyl-, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, —SR⁸, and—OR⁸, wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4-to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and (5- to 10-memberedheteroaryl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting ofhalogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ hydroxylalkyl, C₁₋₄ alkoxy,—N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄ alkyl), C₆₋₁₀ aryloxy,[(C₆₋₁₀ aryl)-C₁₋₄ alkyloxy-optionally substituted with 1 or 2 C₁₋₄alkyl], oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄ alkyl, —C(═O)NH₂,—NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a 5- or 6-memberedheteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or R⁹ and an adjacent R¹⁰ together with the two ring atoms on Q¹ towhich they are attached form a fused benzene ring or a fused 5- or6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(10a); and

each R^(10a) is independently selected from the group consisting ofhalogen, —OH, —N(R⁵)(R⁶), —C(═O)OH, —C(═O)—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, —CN, —SF₅, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄hydroxylalkyl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy, with the provisothat

(1) when X⁴ is N then X¹ is O;(2) when X¹ is NH then X³ is other than N;(3) when X² is C-T², X³ is C-T³, and X⁴ is C-T⁴, then X¹ is other than Sor O;(4) when L¹ is O or NO, X³ is C-T³, and X⁴ is C-T⁴, then X¹ is otherthan NH;(5) when X¹ is NH or O, and at least one of X³ and X⁴ is N, then Q¹ isnot an optionally substituted monocyclic 5-membered ring; and(6) when X⁴ is N and X¹ is O, then L¹ is other than NR^(N).

In some embodiments, when X³ is C-T³ and X⁴ is C-T⁴, then X¹ is otherthan NH.

In some embodiments, when Q¹ is an optionally substituted monocyclicring, then a ring-forming carbon atom of Q¹ is directly linked to thebenzene ring of Formula I that is substituted by R¹, R², R³, and R⁴.

In some embodiments, when a ring-forming nitrogen atom of Q¹ is directlylinked to the benzene ring of Formula I that is substituted by R¹, R²,R³, and R⁴, then Q¹ is an optionally substituted bicyclic ring (e.g., anoptionally substituted bicyclic heteroaryl).

In some embodiments, Q¹ is other than an optionally substitutedmonocyclic 5-membered ring.

In some embodiments, L¹ is other than NR^(N).

In some embodiments, each of the ring-forming atoms of Q¹ is a nitrogenor carbon atom. In some further embodiment, when Q¹ is an optionallysubstituted monocyclic ring, then a ring-forming carbon atom of Q¹ isdirectly linked to the benzene ring that is substituted by R¹, R², R³,and R⁴.

In some embodiments, L¹ is other than NR^(N).

In some embodiments:

(1) when X⁴ is N then X¹ is O;

(2) when X¹ is NH then X³ is other than N;

(3) when X² is C-T², X³ is C-T³, and X⁴ is C-T⁴, then X¹ is other than Sor O;

(4) when X³ is C-T³ and X⁴ is C-T⁴, then X¹ is other than NH;

(5) Q¹ is other than an optionally substituted monocyclic 5-memberedring;

(6) each of the ring-forming atoms of Q¹ is a nitrogen or carbon atom;

(7) when Q¹ is an optionally substituted monocylic ring, then aring-forming carbon atom of Q¹ is directly linked to the benzene ringthat is substituted by R¹, R², R³, and R⁴; and

(8) L¹ is other than NR^(N).

In some embodiments, L¹ is O or S. In some further embodiments, L¹ is S.

In some embodiments, L¹ is O.

In some embodiments, L¹ is NH.

In some embodiments, L¹ is C(═O) or CH(OH).

In some embodiments, each of T², T³, and T⁴ is independently selectedfrom the group consisting of H, halogen, —CN, methoxy, fluoroalkoxy,methyl, and C₁ fluoroalkyl.

In some embodiments, T¹ is H and T⁴ is H.

In some embodiments, each of T² and T³ is independently H, CN, F, Cl,Br, methoxy, C₁ fluoroalkoxy, methyl, or C₁ fluoroalkyl.

In some embodiments, T¹ is H; each of T² and T³ is independently H, F,CI, methoxy, C₁ fluoroalkoxy, methyl, or C₁ fluoroalkyl; and T⁴ is H.

In some embodiments, T² is H and T³ is H.

In some embodiments, X¹ is O.

In some embodiments, X¹ is O; and 0 or 1 of X² and X³ is N. In somefurther embodiments, X⁴ is N.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N, and X⁴ is C-T⁴.

In some embodiments, X¹ is S.

In some embodiments, X¹ is S; and 0 or 1 of X² and X³ is N. In somefurther embodiments, X⁴ is N.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N, and X⁴ is C-T⁴.

In some embodiments, X¹ is NH.

In some embodiments, X¹ is NH; and 0 or 1 of X² and X³ is N. In somefurther embodiments, X⁴ is C-T⁴.

In some embodiments, X¹ is NH; X² is C-T²; and X³ is N.

In some embodiments, X⁴ is N; and X¹ is O or S. In some furtherembodiments, 0 or 1 of X² and X³ is N.

In some embodiments, X⁴ is N; and X¹ is O. In some further embodiments,0 or 1 of X² and X³ is N.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-d:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-e:

or a pharmaceutically acceptable salt thereof.

The embodiments described herein in the second aspect of the invention,unless specified otherwisely, include a compound of Formula I, I-a, I-b,I-c, I-d, or I-e, or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R¹ and R² is independently H or halogen. Insome further embodiments, each of R¹ and R² is H.

In some embodiments, each of R³ and R⁴ is independently H, halogen, —CN,methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy.

In some embodiments, R³ is H and R⁴ is H, halogen, —CN, methyl, or C₁haloalkyl.

In some embodiments, R³ is H and R⁴ is methyl.

In some embodiments, Q¹ is an N-containing 5- to 6-membered heteroarylor an N-containing 5- to 6-membered heterocycloalkyl, each substitutedwith one R⁹ and further optionally substituted with 1, 2, 3, or 4 R¹⁰.

In some embodiments:

Q¹ is a moiety of

ring Q^(1a) is an N-containing 5- to 6-membered heteroaryl or anN-containing 5- to 6-membered heterocycloalkyl;

represents a single bond or double bond;

each of Z¹ and Z² is independently C or N;

R⁹ is halogen (e.g. Cl), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl,—CN, —N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or C₃₋₇ cycloalkoxy,wherein each of the C₁₋₄ alkyl and C₃₋₇ cycloalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents each independentlyselected from the group consisting of halogen, —N(R⁵)(R⁶), C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;

each R¹⁰ is independently selected from the group consisting of halogen,—OH, —CN, —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl,a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5-to 10-membered heteroaryl)-C₁₋₄ alkyl-, (5- to 10-memberedheteroaryl)-C₂₋₄ alkenyl-, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, and —OR⁸,wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4- to10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5- to 10-membered heteroaryl)-C₁₋₄alkyl-, and (5- to 10-membered heteroaryl)-C₂₋₄ alkenyl- is optionallysubstituted with 1, 2, 3, or 4 substituents each independently selectedfrom the group consisting of halogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄hydroxylalkyl, C₁₋₄ alkoxy, —N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄alkyl), C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)-C₁₋₄ alkyloxy-optionally substitutedwith 1 or 2 C₁₋₄ alkyl, oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄alkyl, —C(═O)NH₂, —NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a5- or 6-membered heteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or R⁹ and the adjacent R¹⁰ together with the two ring atoms on ringQ^(1a) to which they are attached form a fused benzene ring or a fused5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3,4, or 5 independently selected R^(10a);

each R^(10a) is independently selected from the group consisting ofhalogen, —OH, —C(═O)OH, —C(═O)—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ hydroxylalkyl, (C₁₋₂alkoxy)-C₁₋₄ alkyl-, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and

m is 0, 1, 2, 3, or 4.

In some embodiment, each R¹⁰ is independently selected from the groupconsisting of halogen, —OH, —CN, —SF_(S), —NO₂, oxo, thiono, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and (C₃₋₇ cycloalkyl)-C₁₋₄alkyl-, wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and (C₃₋₇ cycloalkyl)-C₁₄ alkyl- is optionally substitutedwith 1, 2, 3, 4, or 5 substituents each independently selected from thegroup consisting of halogen, —N(R⁵)(R⁶), C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

In some embodiments, Z¹ is C.

In some embodiments, Q¹ or ring Q^(1a) is an optionally substitutedN-containing 6-membered heteroaryl.

In some embodiments, Q¹ or ring Q^(1a) is an optionally substitutedpyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some furtherembodiments, Q¹ or ring Q^(1a) is an optionally substituted pyrimidinyl,pyridazinyl, or pyrazinyl.

In some embodiments, Q¹ or ring Q^(1a) is pyrimidinyl, pyridazinyl, orpyrazinyl, each of which is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting ofOH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂ alkoxy)-C₁-4 alkyl-, and C₃₋₇cycloalkyl. In some further embodiments, Q¹ or ring Q^(1a) ispyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionallysubstituted with 1, 2, 3, or 4 substituents each independently selectedfrom the group consisting of CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂alkoxy)-C₁₋₄ alkyl-, and C₃₋₇ cycloalkyl. In still further embodiments,Q¹ or ring Q^(1a) is pyrimidinyl, pyridazinyl, or pyrazinyl, each ofwhich is optionally substituted with 1 or 2 substituents eachindependently selected from the group consisting of CN, C₁₋₄ alkyl, andC₁₋₄ haloalkyl. In yet still further embodiments, Q¹ or ring Q^(1a) ispyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of CN and C₁₋₄ alkyl.

In some embodiments, Moiety M¹ is selected from the group consisting ofquinolinyl, isoquinolinyl, 1H-imidazo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl,imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl,9H-purinyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[1,5-a]pyrimidinyl, isoxazolo[5,4-c]pyridazinyl,isoxazolo[3,4-c]pyridazinyl, and [1,2,4]triazolo[4,3-b]pyridazinyl, eachoptionally substituted with 1, 2, or 3 R¹⁰ and further optionallysubstituted with 1 or 2 R^(10a); or wherein Moiety M¹ is selected fromthe group consisting of pyrimidinyl, pyrazinyl, pyridinyl, pyridazinyl,1H-pyrazolyl, 1H-pyrrolyl, 4H-pyrazolyl, 1H-imidazolyl, 1H-imidazolyl,3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl,2,4(1H,3H)-dioxo-pyrimidinyl, and 1H-2-oxo-pyrazinyl, each substitutedwith R⁹ and further optionally substituted with 1, 2, or 3 R¹⁰.

In some embodiments:

Moiety M¹ is

R^(10a) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, orC₃₋₇ cycloalkyl;

t1 is 0 or 1; and

t is 0 or 1.

In some embodiments, Moiety M¹ is

In some embodiments, Moiety M¹ is

In some embodiments:

Moiety M¹ is

and

R¹¹ is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, or C₃₋₇cycloalkyl.

In some embodiments, R⁹ is halogen (e.g., Cl), C₃₋₆ cycloalkyl (e.g.,cyclopropyl), C₁₋₄ alkyl, or —CN. In some further embodiments, R⁹ ishalogen (e.g., Cl), C₁₋₄ alkyl, or —CN.

In some embodiments, R⁹ is C₁₋₄ alkyl or —CN. In some furtherembodiments, R⁹ is C₁₋₄ alkyl. In some yet further embodiments, R⁹ ismethyl.

In some embodiments, each R¹⁰ is independently selected from the groupconsisting of halogen, —OH, —CN, —SF₅, —NO₂, oxo, thiono, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and (C₃₋₇ cycloalkyl)-C₁₋₄alkyl-, wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and (C₃₋₇ cycloalkyl)-C₁₄ alkyl- is optionally substitutedwith 1, 2, 3, 4, or 5 substituents each independently selected from thegroup consisting of halogen, —N(R⁵)(R⁶), C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

In some embodiments, each R¹⁰ is independently selected from the groupconsisting of —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxylalkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-,and —N(R⁵)(R⁶), wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and (C₃₋₇ cycloalkyl)-C₁₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents each independentlyselected from the group consisting of halogen, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy. In some further embodiments, each R¹⁰ is independentlyselected from the group consisting of —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxylalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, and C₃₋₄ cycloalkyl, and—N(R⁵)(R⁶).

In some embodiments, each R¹⁰ is independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-,—CN, and —N(R⁵)(R⁶), wherein each of R⁵ and R⁶ independently is H orselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, andC₃₋₇ cycloalkyl; or R⁵ and R⁶ together with the N atom to which they areattached form a 4- to 7-membered heterocycloalkyl or a 5-memberedheteroaryl, each optionally substituted with 1, 2, or 3 substituentseach independently selected from the group consisting of halogen, —CN,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy. In some further embodiments, each R¹⁰ is independently C₁₋₄alkyl or CN. In yet further embodiments, each R¹⁰ is independently C₁₋₄alkyl. In still yet further embodiments, each R¹⁰ is methyl.

In some embodiments, each of R⁹ and R¹⁰ is independently halogen (e.g.,Cl), C₃₋₆ cycloalkyl (e.g., cyclopropyl), C₁₋₄ alkyl, or —CN. In somefurther embodiments, each of R⁹ and R¹⁰ is independently halogen (e.g.,Cl), C₁₋₄ alkyl, or —CN.

In some embodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl orCN. In some further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; X⁴ is N; Q¹ is M¹; and M¹ is as described inone of the embodiments provided herein (e.g., M¹-g, M¹-k, M¹-m, orM¹-n). In some further embodiments, L¹ is O or S. In yet furtherembodiments, L¹ is O. In still further embodiments, each of R¹ and R² isindependently H or halogen; and each of R³ and R⁴ is independently H,halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yetstill further embodiments, each of R¹ and R² is H; R³ is H; and R⁴ ismethyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is as described in one of theembodiments provided herein (e.g.; M¹-g, M¹-k, M¹-m, or M¹-n). In somefurther embodiments, L¹ is O or S. In yet further embodiments, L¹ is O.In still further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is N, X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is O; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; X⁴ is N; Q¹ is M¹; and M¹ is as described inone of the embodiments provided herein (e.g., M¹-k, M¹-m, or M¹-n). Insome further embodiments, L¹ is O or S. In yet further embodiments, L¹is O. In still further embodiments, each of R¹ and R² is independently Hor halogen; and each of R³ and R⁴ is independently H, halogen, —CN,methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 0 or 1 of X² and X³ is N (e.g., neither ofX² and X³ is N); X⁴ is N; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, orhaloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is 0.

In still further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is as described in one of theembodiments provided herein (e.g.; M¹-g, M¹-k, M¹-m, or M¹-n). In somefurther embodiments, L¹ is O or S. In yet further embodiments, L¹ is O.In still further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; 1 of X² and X³ is N (e.g., X² is N and X³is C-T³); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is N, X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is S; X² is C-T², X³ is C-T³; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is as described in oneof the embodiments provided herein (e.g., M¹-g, M¹-k, M¹-m, or M¹-n). Insome further embodiments, L¹ is O or S. In yet further embodiments, L¹is O. In still further embodiments, each of R¹ and R² is independently Hor halogen; and each of R³ and R⁴ is independently H, halogen, —CN,methyl, C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet still furtherembodiments, each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-g. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-k. In some furtherembodiments, L¹ is O or S.

In yet further embodiments, L¹ is O. In still further embodiments, eachof R¹ and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-m. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; 0 or 1 of X² and X³ is N (e.g., X² isC-T² and X³ is N); X⁴ is C-T⁴; Q¹ is M¹; and M¹ is M¹-n. In some furtherembodiments, L¹ is O or S. In yet further embodiments, L¹ is O. In stillfurther embodiments, each of R¹ and R² is independently H or halogen;and each of R³ and R⁴ is independently H, halogen, —CN, methyl, C₁haloalkyl, methoxy, or C₁ haloalkoxy. In yet still further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-g. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-k. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-m. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, X¹ is NH; X² is C-T², X³ is N; X⁴ is N; Q¹ is M¹;and M¹ is M¹-n. In some further embodiments, L¹ is O or S. In yetfurther embodiments, L¹ is O. In still further embodiments, each of R¹and R² is independently H or halogen; and each of R³ and R⁴ isindependently H, halogen, —CN, methyl, C₁ haloalkyl, methoxy, or C₁haloalkoxy. In yet still further embodiments, each of R¹ and R² is H; R³is H; and R⁴ is methyl.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-a or a salt thereof; and Q¹ is M¹; and M¹ is M¹-g.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-a or a salt thereof; and Q¹ is M¹; and M¹ is M¹-k.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-a or a salt thereof; and Q¹ is M¹; and M¹ is M¹-m.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-a or a salt thereof; and Q¹ is M¹; and M¹ is M¹-n.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-b or a salt thereof; and Q¹ is M¹; and M¹ is M¹-g.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-b or a salt thereof; and Q¹ is M¹; and M¹ is M¹-k.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-b or a salt thereof; and Q¹ is M¹; and M¹ is M¹-m.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-b or a salt thereof; and Q¹ is M¹; and M¹ is M¹-m.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-c or a salt thereof; and Q¹ is M¹; and M¹ is M¹-g.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-c or a salt thereof; and Q¹ is M¹; and M¹ is M¹-k.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-c or a salt thereof; and Q¹ is M¹; and M¹ is M¹-m.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-c or a salt thereof; and Q¹ is M¹; and M¹ is M¹-n.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-d or a salt thereof; and Q¹ is M¹; and M¹ is M¹-g.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-d or a salt thereof; and Q¹ is M¹; and M¹ is M¹-k.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-d or a salt thereof; and Q¹ is M¹; and M¹ is M¹-m.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-d or a salt thereof; and Q¹ is M¹; and M¹ is M¹-n.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-e or a salt thereof; and Q¹ is M¹; and M¹ is M¹-g.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-e or a salt thereof; and Q¹ is M¹; and M¹ is M¹-k.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-e or a salt thereof; and Q¹ is M¹; and M¹ is M¹-m.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁰ is independentlymethyl or CN.

In some embodiments, the compound of Formula I or a salt thereof is acompound of Formula I-e or a salt thereof; and Q¹ is M¹; and M¹ is M¹-n.In some further embodiments, each of R¹ and R² is independently H orhalogen; and each of R³ and R⁴ is independently H, halogen, —CN, methyl,C₁ haloalkyl, methoxy, or C₁ haloalkoxy. In yet further embodiments,each of R¹ and R² is H; R³ is H; and R⁴ is methyl. In some still furtherembodiments, each of R⁹ and R¹⁰ is independently C₁₋₄ alkyl or CN. Inyet still further embodiments, each of R⁹ and R¹⁹ is independentlymethyl or CN.

In some embodiments, the invention also provides one or more of thecompounds described in Examples 1-23 in the Examples section of thesubject application, pharmaceutically acceptable salts of the compounds;or the N-oxides of the compound or salt.

In some embodiments, the present invention provides a compound selectedfrom the group consisting of:

-   4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[2,3-d]pyrimidine;-   6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one;-   (−)-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one;-   (+)-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one;-   5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one;-   (+)-5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one;-   (−)-5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one;-   6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;-   5-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one;    5-ethyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1-methylpyrimidine-2,4(1H,3H)-dione;-   1-ethyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-5-methylpyrimidine-2,4(1H,3H)-dione;    and-   1-cyclopropyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-5-methylpyrimidine-2,4(1H,3H)-dione,    or a pharmaceutically acceptable salt thereof.    The second aspect of the invention includes any subset of any    embodiment described herein.

The second aspect of the invention includes combinations of two or moreembodiments described hereinabove, or any subset thereof.

The second aspect of the invention further provides the compound ofFormula I or a pharmaceutically acceptable salt thereof (including allembodiments and combinations of two or more embodiments described hereinor any subcombination thereof) for use in treating a D1-mediated (orD1-associated) disorder described herein. The second aspect of theinvention further provides use of the compound of Formula I or apharmaceutically acceptable salt thereof (including all embodiments andcombinations of two or more embodiments described herein or anysubcombination thereof) for treating a D1-mediated (or D1-associated)disorder described herein.

The second aspect of the invention further provides use of the compoundof Formula I or a pharmaceutically acceptable salt thereof (includingall embodiments and combinations of two or more embodiments describedherein or any subcombination thereof) in manufacturing a medicament foruse in treating a D1-mediated (or D1-associated) disorder describedherein.

The compound of Formula I or its salt of the second aspect of presentinvention is a D1R modulator (e.g., a D1R agonist for example, a D1Rpartial agonist). Thus, the second aspect of present invention furtherprovides a method for modulating (such as agonizing or partiallyagonizing) an activity of D1R (either in vitro or in vivo), comprisingcontacting (including incubating) the D1R with a compound of Formula Ior a pharmaceutically acceptable salt thereof (such as one selected fromExamples 1-23 herein) described herein.

As used herein, the term “n-membered” where n is an integer typicallydescribes the number of ring-forming atoms in a moiety where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiophene is an example of a 5-memberedheteroaryl group.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to include C₁alkyl (methyl), C₂ alkyl (ethyl), C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆alkyl. For another example, the term “a 5- to 10-membered heteroarylgroup” is specifically intended to include any 5-, 6-, 7-, 8-, 9- or10-membered heteroaryl group.

As used herein, the term “alkyl” is defined to include saturatedaliphatic hydrocarbons including straight chains and branched chains. Insome embodiments, the alkyl group has 1 to 20 carbon atoms, 1 to 10carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. For example,the term “C₁₋₆ alkyl,” as well as the alkyl moieties of other groupsreferred to herein (e.g., C₁₋₆alkoxy) refers to linear or branchedradicals of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, orn-hexyl). For yet another example, the term “C₁₋₄ alkyl” refers tolinear or branched aliphatic hydrocarbon chains of 1 to 4 carbon atoms;the term “C₁₋₃ alkyl” refers to linear or branched aliphatic hydrocarbonchains of 1 to 3 carbon atoms; the term “C₁₋₂ alkyl” refers to linear orbranched aliphatic hydrocarbon chains of 1 to 2 carbon atoms; and theterm “C₁ alkyl” refers to methyl. An alkyl group optionally can besubstituted by one or more (e.g. 1 to 5) suitable substituents.

As used herein, the term “alkenyl” refers to aliphatic hydrocarbonshaving at least one carbon-carbon double bond, including straight chainsand branched chains having at least one carbon-carbon double bond. Insome embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbonatoms. For example, as used herein, the term “C₂₋₆ alkenyl” meansstraight or branched chain unsaturated radicals (having at least onecarbon-carbon double bond) of 2 to 6 carbon atoms, including, but notlimited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. An alkenylgroup optionally can be substituted by one or more (e.g. 1 to 5)suitable substituents. When the compounds of Formula I contain analkenyl group, the alkenyl group may exist as the pure E form, the pureZ form, or any mixture thereof.

As used herein, the term “alkynyl” refers to aliphatic hydrocarbonshaving at least one carbon-carbon triple bond, including straight chainsand branched chains having at least one carbon-carbon triple bond. Insome embodiments, the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3to 6 carbon atoms. For example, as used herein, the term “C₂₋₆ alkynyl”refers to straight or branched hydrocarbon chain alkynyl radicals asdefined above, having 2 to 6 carbon atoms. An alkynyl group optionallycan be substituted by one or more (e.g. 1 to 5) suitable substituents.

As used herein, the term “cycloalkyl” refers to saturated orunsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic)hydrocarbon rings (e.g., monocyclics such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, orbicyclics including spiro, fused, or bridged systems (such asbicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl orbicyclo[5.2.0]nonanyl, decahydronaphthalenyl, etc.). The cycloalkylgroup has 3 to 15 carbon atoms. In some embodiments the cycloalkyl mayoptionally contain one, two or more non-cumulative non-aromatic doubleor triple bonds and/or one to three oxo groups. In some embodiments, thebicycloalkyl group has 6 to 14 carbon atoms. For example, the term“C₃₋₁₄ cycloalkyl” refers to saturated or unsaturated, non-aromatic,monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 14ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[1.1.1]pentanyl, or cyclodecanyl); and the term “C₃₋₇cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclicor polycyclic (such as bicyclic) hydrocarbon rings of 3 to 7ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, bicyclo[1.1.1]pentan-1-yl, or bicyclo[1.1.1]pentan-2-yl).For another example, the term “C₃₋₆ cycloalkyl” refers to saturated orunsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic)hydrocarbon rings of 3 to 6 ring-forming carbon atoms. For yet anotherexample, the term “C₃₋₄ cycloalkyl” refers to cyclopropyl or cyclobutyl.Also included in the definition of cycloalkyl are moieties that have oneor more aromatic rings (including aryl and heteroaryl) fused to thecycloalkyl ring, for example, benzo or thienyl derivatives ofcyclopentane, cyclopentene, cyclohexane, and the like (e.g.,2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl). The cycloalkylgroup optionally can be substituted by 1 or more (e.g., 1 to 5) suitablesubstituents.

As used herein, the term “aryl” refers to all-carbon monocyclic orfused-ring polycyclic aromatic groups having a conjugated pi-electronsystem. The aryl group has 6 or 10 carbon atoms in the ring(s). Mostcommonly, the aryl group has 6 carbon atoms in the ring. For example, asused herein, the term “C₆₋₁₀ aryl” means aromatic radicals containingfrom 6 to 10 carbon atoms such as phenyl or naphthyl. The aryl groupoptionally can be substituted by 1 or more (e.g., 1 to 5) suitablesubstituents.

As used herein, the term “heteroaryl” refers to monocyclic or fused-ringpolycyclic aromatic heterocyclic groups with one or more heteroatom ringmembers (ring-forming atoms) each independently selected from O, S and Nin at least one ring. The heteroaryl group has 5 to 14 ring-formingatoms, including 1 to 13 carbon atoms, and 1 to 8 heteroatoms selectedfrom O, S, and N. In some embodiments, the heteroaryl group has 5 to 10ring-forming atoms including one to four heteroatoms. The heteroarylgroup can also contain one to three oxo or thiono (i.e. ═S) groups. Insome embodiments, the heteroaryl group has 5 to 8 ring-forming atomsincluding one, two or three heteroatoms. For example, the term“5-membered heteroaryl” refers to a monocyclic heteroaryl group asdefined above with 5 ring-forming atoms in the monocyclic heteroarylring; the term “6-membered heteroaryl” refers to a monocyclic heteroarylgroup as defined above with 6 ring-forming atoms in the monocyclicheteroaryl ring; and the term “5- or 6-membered heteroaryl” refers to amonocyclic heteroaryl group as defined above with 5 or 6 ring-formingatoms in the monocyclic heteroaryl ring. For another example, term “5-or 10-membered heteroaryl” refers to a monocyclic or bicyclic heteroarylgroup as defined above with 5, 6, 7, 8, 9 or 10 ring-forming atoms inthe monocyclic or bicyclic heteroaryl ring. A heteroaryl groupoptionally can be substituted by 1 or more (e.g., 1 to 5) suitablesubstituents. Examples of monocyclic heteroaryls include those with 5ring-forming atoms including one to three heteroatoms or those with 6ring-forming atoms including one, two or three nitrogen heteroatoms.Examples of fused bicyclic heteroaryls include two fused 5- and/or6-membered monocyclic rings including one to four heteroatoms.

Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g.,1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl,1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl,benzofuryl, indolyl, 1H-imidazo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl,imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl,9H-purinyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4-c]pyridazinyl, pyridone,pyrimidone, pyrazinone, pyrimidinone, 1H-imidazol-2(3H)-one,1H-pyrrole-2,5-dione, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl,1H-2-oxo-pyridinyl, 2,4(1H,3H)-dioxo-pyrimidinyl, 1H-2-oxo-pyrazinyl,and the like. The heteroaryl group optionally can be substituted by 1 ormore (e.g., 1 to 5) suitable substituents.

As used herein, the term “heterocycloalkyl” refers to a monocyclic orpolycyclic [including 2 or more rings that are fused together, includingspiro, fused, or bridged systems, for example, a bicyclic ring system],saturated or unsaturated, non-aromatic 4- to 15-membered ring system(such as a 4- to 14-membered ring system, 4- to 12-membered ring system,5- to 10-membered ring system, 4- to 7-membered ring system, 4- to6-membered ring system, or 5- to 6-membered ring system), including 1 to14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms eachindependently selected from O, S and N. The heterocycloalkyl group canalso optionally contain one or more oxo or thiono (i.e. ═S) groups. Forexample, the term “4- to 12-membered heterocycloalkyl” refers to amonocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to12-membered ring system that comprises one or more ring-formingheteroatoms each independently selected from O, S and N; and the term“4- to 10-membered heterocycloalkyl” refers to a monocyclic orpolycyclic, saturated or unsaturated, non-aromatic 4- to 10-memberedring system that comprises one or more ring-forming heteroatoms eachindependently selected from O, S and N. For another example, the term“4- to 6-membered heterocycloalkyl” refers to a monocyclic orpolycyclic, saturated or unsaturated, non-aromatic 4- to 6-membered ringsystem that comprises one or more ring-forming heteroatoms eachindependently selected from O, S and N; and the term “5- to 6-memberedheterocycloalkyl” refers to a monocyclic or polycyclic, saturated orunsaturated, non-aromatic 5- to 6-membered ring system that comprisesone or more ring-forming heteroatoms each independently selected from O,S and N. Also included in the definition of heterocycloalkyl aremoieties that have one or more aromatic rings (including aryl andheteroaryl) fused to the nonaromatic heterocycloalkyl ring, for examplepyridinyl, pyrimidinyl, thiophenyl, pyrazolyl, phthalimidyl,naphthalimidyl, and benzo derivatives of the nonaromaticheterocycloalkyl rings. The heterocycloalkyl group optionally can besubstituted by 1 or more (e.g., 1 to 5) suitable substituents.

Examples of such heterocycloalkyl rings include azetidinyl,tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl,morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl,quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl,7-azabicyclo[2.2.1]heptan-1-yl, 7-azabicyclo[2.2.1]heptan-2-yl,7-azabicyclo[2.2.1]heptan-7-yl, 2-azabicyclo[2.2.1]heptan-3-on-2-yl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the like.Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4-oxazepan-1-yl,isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl,oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), and thelike. Some examples of aromatic-fused heterocycloalkyl groups includeindolinyl, isoindolinyl, isoindolin-1-one-3-yl,5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl,6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl,1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-yl, and3,4-dihydroisoquinolin-1(2H)-one-3-yl groups. The heterocycloalkyl groupis optionally substituted by 1 or more (e.g., 1 to 5) suitablesubstituents. Examples of heterocycloalkyl groups include 5- or6-membered monocyclic rings and 9- or 10-membered fused bicyclic rings.

As used herein, the term “halo” or “halogen” group is defined to includefluorine, chlorine, bromine or iodine.

As used herein, the term “haloalkyl” refers to an alkyl group having oneor more halogen substituents (up to perhaloalkyl, i.e., every hydrogenatom of the alkyl group has been replaced by a halogen atom). Forexample, the term “C₁₋₆ haloalkyl” refers to a C₁₋₆ alkyl group havingone or more halogen substituents (up to perhaloalkyl, i.e., everyhydrogen atom of the alkyl group has been replaced by a halogen atom).For another example, the term “C₁₋₄ haloalkyl” refers to a C₁₋₄ alkylgroup having one or more halogen substituents (up to perhaloalkyl, i.e.,every hydrogen atom of the alkyl group has been replaced by a halogenatom); the term “C₁₋₃ haloalkyl” refers to a C₁₋₃ alkyl group having oneor more halogen substituents (up to perhaloalkyl, i.e., every hydrogenatom of the alkyl group has been replaced by a halogen atom); and theterm “C₁₋₂ haloalkyl” refers to a C₁₋₂ alkyl group (i.e. methyl orethyl) having one or more halogen substituents (up to perhaloalkyl,i.e., every hydrogen atom of the alkyl group has been replaced by ahalogen atom). For yet another example, the term “C₁ haloalkyl” refersto a methyl group having one, two, or three halogen substituents.Examples of haloalkyl groups include CF₃, C₂F₅, CHF₂, CH₂F, CH₂CF₃,CH₂Cl and the like.

As used herein, the term “halocycloalkyl” refers to a cycloalkyl grouphaving one or more halogen substituents (up to perhalocycloalkyl, i.e.,every hydrogen atom of the cycloalkyl group has been replaced by ahalogen atom). For example, the term “C₃₋₄ halocycloalkyl” refers to acyclopropyl or cyclobutyl group having one or more halogen substituents.An example of halocycloalkyl is 2-fluorocyclopropan-1-yl.

As used herein, the term “alkoxy” or “alkyloxy” refers to an —O-alkylgroup. For example, the term “C₁₋₆ alkoxy” or “C₁₋₆ alkyloxy” refers toan —O—(C₁₋₆ alkyl) group; and the term “C₁₋₄ alkoxy” or “C₁₋₄ alkyloxy”refers to an —O—(C₁₋₄ alkyl) group; For another example, the term “C₁₋₂alkoxy” or “C₁₋₂ alkyloxy” refers to an —O—(C₁₋₂ alkyl) group. Examplesof alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), tert-butoxy, and the like. The alkoxy or alkyloxy groupoptionally can be substituted by 1 or more (e.g., 1 to 5) suitablesubstituents.

As used here, the term “haloalkoxy” refers to an —O-haloalkyl group. Forexample, the term “C₁₋₆ haloalkoxy” refers to an —O—(C₁₋₆ haloalkyl)group. For another example, the term “C₁₋₄ haloalkoxy” refers to an—O—(C₁₋₄ haloalkyl) group; and the term “C₁₋₂ haloalkoxy” refers to an—O—(C₁₋₂ haloalkyl) group. For yet another example, the term “C₁haloalkoxy” refers to a methoxy group having one, two, or three halogensubstituents. An example of haloalkoxy is —OCF₃ or —OCHF₂.

As used herein, the term “cycloalkoxy” or “cycloalkyloxy” refers to an—O— cycloalkyl group. For example, the term “C₃₋₇ cycloalkoxy” or “C₃₋₇cycloalkyloxy” refers to an —O—(C₃₋₇ cycloalkyl) group. For anotherexample, the term “C₃₋₆ cycloalkoxy” or “C₃₋₆ cycloalkyloxy” refers toan —O—(C₃₋₆ cycloalkyl) group. Examples of cycloalkoxy include C₃₋₆cycloalkoxy (e.g., cyclopropoxy, cyclobutoxy, cyclopentoxy,cyclohexanoxy, and the like). The cycloalkoxy or cycloalkyloxy groupoptionally can be substituted by 1 or more (e.g., 1 to 5) suitablesubstituents.

As used here, the term “C₆₋₁₀ aryloxy” refers to an —O—(C₆₋₁₀ aryl)group. An example of a C₆₋₁₀ aryloxy group is —O-phenyl [i.e., phenoxy].The C₆₋₁₀ aryloxy y group optionally can be substituted by 1 or more(e.g., 1 to 5) suitable substituents.

As used herein, the term “fluoroalkyl” refers to an alkyl group havingone or more fluorine substituents (up to perfluoroalkyl, i.e., everyhydrogen atom of the alkyl group has been replaced by fluorine). Forexample, the term “C₁₋₂ fluoroalkyl” refers to a C₁₋₂ alkyl group havingone or more fluorine substituents (up to perfluoroalkyl, i.e., everyhydrogen atom of the C₁₋₂ alkyl group has been replaced by fluorine).For another example, the term “C₁ fluoroalkyl” refers to a C₁ alkylgroup (i.e., methyl) having 1, 2, or 3 fluorine substituents). Examplesof fluoroalkyl groups include CF₃, C₂F₅, CH₂CF₃, CHF₂, CH₂F, and thelike.

As used here, the term “fluoroalkoxy” refers to an —O-fluoroalkyl group.For example, the term “C₁₋₂ fluoroalkoxy” refers to an —O—C₁₋₂fluoroalkyl group. For another example, the term “C₁ fluoroalkoxy”refers to a methoxy group having one, two, or three fluorinesubstituents. An example of C₁ fluoroalkoxy is —OCF₃ or —OCHF₂.

As used herein, the term “hydroxylalkyl” or “hydroxyalkyl” refers to analkyl group having one or more (e.g., 1, 2, or 3) OH substituents. Theterm “C₁₋₆ hydroxylalkyl” or “C₁₋₆ hydroxyalkyl” refers to a C₁₋₆ alkylgroup having one or more (e.g., 1, 2, or 3) OH substituents. The term“C₁₋₄ hydroxylalkyl” or “C₁₋₄ hydroxyalkyl” refers to a C₁₋₄ alkyl grouphaving one or more (e.g., 1, 2, or 3) OH substituents; the term “C₁₋₃hydroxylalkyl” or “C₁₋₃ hydroxyalkyl” refers to a C₁₋₃ alkyl grouphaving one or more (e.g., 1, 2, or 3) OH substituents; and the term“C₁₋₂ hydroxylalkyl” or “C₁₋₂ hydroxyalkyl” refers to a C₁₋₂ alkyl grouphaving one or more (e.g., 1, 2, or 3) OH substituents. An example ofhydroxylalkyl is —CH₂OH or —CH₂CH₂OH.

As used herein, the term “oxo” refers to ═O. When an oxo is substitutedon a carbon atom, they together form a carbonyl moiety [—C(═O)—]. Whenan oxo is substituted on a sulfur atom, they together form a sulfinylmoiety [—S(═O)—]; when two oxo groups are substituted on a sulfur atom,they together form a sulfonyl moiety [—S(═O)₂—].

As used herein, the term “thiono” refers to ═S. When an thiono issubstituted on a carbon atom, they together form moiety of [—C(═S)—].

As used herein, the term “optionally substituted” means thatsubstitution is optional and therefore includes both unsubstituted andsubstituted atoms and moieties. A “substituted” atom or moiety indicatesthat any hydrogen on the designated atom or moiety can be replaced witha selection from the indicated substituent group (up to that everyhydrogen atom on the designated atom or moiety is replaced with aselection from the indicated substituent group), provided that thenormal valency of the designated atom or moiety is not exceeded, andthat the substitution results in a stable compound. For example, if amethyl group (i.e., CH₃) is optionally substituted, then up to 3hydrogen atoms on the carbon atom can be replaced with substituentgroups.

As used herein, the term “optionally substituted C₁₋₄ alkyl” refers toC₁₋₄ alkyl optionally substituted by one or more (e.g. 1 to 5)substituents each independently selected from the group consisting of—OH, halogen, —CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy.

As used herein, the term “optionally substituted C₁₋₂ alkyl” refers toC₁₋₂ alkyl optionally substituted by one or more (e.g. 1 to 5)substituents each independently selected from the group consisting of—OH, halogen, —CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy.

As used herein, the term “optionally substituted C₃₋₄ cycloalkyl” refersto C₃₋₄ cycloalkyl optionally substituted by one or more (e.g. 1 to 5)substituents each independently selected from the group consisting of—OH, halogen, —CN, —NH₂, —NH₂ (C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ hydroxylalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

As used herein, the term “optionally substituted cyclopropylmethyl”refers to cyclopropylmethyl optionally substituted by one or more (e.g.1 to 5) substituents each independently selected from the groupconsisting of —OH, halogen, —CN, —NH₂, —NH₂ (C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxylalkyl, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy.

As used herein, the term “optionally substituted C₁₋₄ alkoxy” refers toC₁₋₄ alkoxy optionally substituted by one or more (e.g. 1 to 5)substituents each independently selected from the group consisting of—OH, halogen, —CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy.

As used herein, unless specified, the point of attachment of asubstituent can be from any suitable position of the substituent. Forexample, piperidinyl can be piperidin-1-yl (attached through the N atomof the piperidinyl), piperidin-2-yl (attached through the C atom at the2-position of the piperidinyl), piperidin-3-yl (attached through the Catom at the 3-position of the piperidinyl), or piperidin-4-yl (attachedthrough the C atom at the 4-position of the piperidinyl). For anotherexample, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl),3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any of thering-forming atoms in that ring that are substitutable (i.e., bonded toone or more hydrogen atoms), unless otherwise specified or otherwiseimplicit from the context. For example, as shown in Formula a-101 below,R¹⁰ may be bonded to either of the two ring carbon atoms each of whichbears a hydrogen atom (but not shown). For another example, as shown inFormula a-102 below, R¹⁰ may be bonded to either of the two ring carbonatoms on the pyrazine ring each of which bears a hydrogen atom (but notshown); and R^(10a) may be bonded to either of the two ring carbon atomson the imidazole ring each of which bears a hydrogen atom (but notshown).

When a substituted or optionally substituted moiety is described withoutindicating the atom via which such moiety is bonded to a substituent,then the substituent may be bonded via any appropriate atom in suchmoiety. For example in a substituted arylalkyl, a substituent on thearylalkyl [e.g., (C₆₋₁₀ aryl)-C₁₋₄ alkyl-] can be bonded to any carbonatom on the alkyl part or on the aryl part of the arylalkyl.Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

As noted above, the compounds of Formula I may exist in the form ofpharmaceutically acceptable salts such as acid addition salts and/orbase addition salts of the compounds of Formula I. The phrase“pharmaceutically acceptable salt(s)”, as used herein, unless otherwiseindicated, includes acid addition or base salts which may be present inthe compounds of Formula I.

Pharmaceutically acceptable salts of the compounds of Formula I includethe acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulfate/sulfate, borate,camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate,fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate,hibenzate, hydrochloride/chloride, hydrobromide/bromide,hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate,mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate,orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate,succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoatesalts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002).Methods for making pharmaceutically acceptable salts of compounds ofFormula I are known to one of skill in the art.

As used herein the terms “Formula I”, “Formula I or pharmaceuticallyacceptable salts thereof”, “pharmaceutically acceptable salts of thecompound or the salt [of Formula I]” are defined to include all forms ofthe compound of Formula I, including hydrates, solvates, isomers(including for example rotational stereoisomers), crystalline andnon-crystalline forms, isomorphs, polymorphs, metabolites, and prodrugsthereof.

As it is known to the person skilled in the art, amine compounds (i.e.,those comprising one or more nitrogen atoms), for example tertiaryamines, can form N-oxides (also known as amine oxides or amineN-oxides). An N-oxide has the formula of (R¹⁰⁰R²⁰⁰R³⁰⁰)N⁺—O⁻ wherein theparent amine (R¹⁰⁰R²⁰⁰R³⁰⁰)N can be for example, a tertiary amine (forexample, each of R¹⁰⁰, R²⁰⁰, R³⁰⁰ is independently alkyl, arylalkyl,aryl, heteroaryl, or the like), a heterocyclic or heteroaromatic amine[for example, (R¹⁰⁰R²⁰⁰R³⁰⁰)N together forms 1-alkylpiperidine,1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyridine]. For instance, animine nitrogen, especially heterocyclic or heteroaromatic iminenitrogen, or pyridine-type nitrogen

atom [such as a nitrogen atom in pyridine, pyridazine, or pyrazine], canbe N-oxidized to form the N-oxide comprising the group

Thus, a compound according to the present invention comprising one ormore nitrogen atoms (e.g., an imine nitrogen atom) may be capable offorming an N-oxide thereof (e.g., mono-N-oxides, bis-N-oxides ormulti-N-oxides, or mixtures thereof depending on the number of nitrogenatoms suitable to form stable N-oxides).

As used herein, the term “N-oxide(s)” refer to all possible, and inparticular all stable, N-oxide forms of the amine compounds (e.g.,compounds comprising one or more imine nitrogen atoms) described herein,such as mono-N-oxides (including different isomers when more than onenitrogen atom of an amine compound can form a mono-N-oxide) ormulti-N-oxides (e.g., bis-N-oxides), or mixtures thereof in any ratio.

Compounds of Formula I and their salts described herein further includeN-oxides thereof.

Compounds of Formula I (including salts thereof) may exist in acontinuum of solid states ranging from fully amorphous to fullycrystalline. The term ‘amorphous’ refers to a state in which thematerial lacks long-range order at the molecular level and, dependingupon temperature, may exhibit the physical properties of a solid or aliquid. Typically such materials do not give distinctive X-raydiffraction patterns and, while exhibiting the properties of a solid,are more formally described as a liquid. Upon heating, a change fromapparent solid to a material with liquid properties occurs, which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (‘Meltingpoint’).

Compounds of Formula I (including salts thereof) may exist in unsolvatedand solvated forms. When the solvent or water is tightly bound, thecomplex will have a well-defined stoichiometry independent of humidity.When, however, the solvent or water is weakly bound, as in channelsolvates and hygroscopic compounds, the water/solvent content will bedependent on humidity and drying conditions. In such cases,non-stoichiometry will be the norm.

The compounds of Formula I (including salts thereof) may exist asclathrates or other complexes (e.g., co-crystals). Included within thescope of the invention are complexes such as clathrates, drug-hostinclusion complexes wherein the drug and host are present instoichiometric or non-stoichiometric amounts. Also included arecomplexes of the compounds of Formula I containing two or more organicand/or inorganic components, which may be in stoichiometric ornon-stoichiometric amounts. The resulting complexes may be ionized,partially ionized, or non-ionized. Co-crystals are typically defined ascrystalline complexes of neutral molecular constituents that are boundtogether through non-covalent interactions, but could also be a complexof a neutral molecule with a salt. Co-crystals may be prepared by meltcrystallization, by recrystallization from solvents, or by physicallygrinding the components together; see O. Almarsson and M. J. Zaworotko,Chem. Commun. 2004, 17, 1889-1896. For a general review ofmulti-component complexes, see J. K. Haleblian, J. Pharm. Sci. 1975, 64,1269-1288.

The compounds of the invention (including salts thereof) may also existin a mesomorphic state (mesophase or liquid crystal) when subjected tosuitable conditions. The mesomorphic state is intermediate between thetrue crystalline state and the true liquid state (either melt orsolution). Mesomorphism arising as the result of a change in temperatureis described as ‘thermotropic’ and that resulting from the addition of asecond component, such as water or another solvent, is described as‘lyotropic’. Compounds that have the potential to form lyotropicmesophases are described as ‘amphiphilic’ and consist of molecules whichpossess an ionic (such as —COO⁻Na⁺, —COO⁻K⁺, or —SO₃Na⁺) or non-ionic(such as —N⁻N⁺(CH₃)₃) polar head group. For more information, seeCrystals and the Polarizing Microscope by N. H. Hartshorne and A.Stuart, 4^(th) Edition (Edward Arnold, 1970).

The invention also relates to prodrugs of the compounds of Formula I.Thus certain derivatives of compounds of Formula I which may have littleor no pharmacological activity themselves can, when administered into oronto the body, be converted into compounds of Formula I having thedesired activity, for example, by hydrolytic cleavage. Such derivativesare referred to as “prodrugs”. Further information on the use ofprodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14,ACS Symposium Series (T. Higuchi and W. Stella) and BioreversibleCarriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, AmericanPharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds ofFormula I with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985), or in Prodrugs: Challenges and Reward, 2007edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman,Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer,2007).

Moreover, certain compounds of Formula I may themselves act as prodrugsof other compounds of Formula I.

Also included within the scope of the invention are metabolites ofcompounds of Formula I, that is, compounds formed in vivo uponadministration of the drug.

The compounds of Formula I (including salts thereof) include allstereoisomers and tautomers. Stereoisomers of Formula I include cis andtrans isomers, optical isomers such as R and S enantiomers,diastereomers, geometric isomers, rotational isomers, atropisomers, andconformational isomers of the compounds of Formula I, includingcompounds exhibiting more than one type of isomerism; and mixturesthereof (such as racemates and diastereomeric pairs). Also included areacid addition or base addition salts wherein the counterion is opticallyactive, for example, D-lactate or L-lysine, or racemic, for example,DL-tartrate or DL-arginine.

In some embodiments, the compounds of Formula I (including saltsthereof) may have asymmetric carbon atoms. The carbon-carbon bonds ofthe compounds of Formula I may be depicted herein using a solid line (

) a solid wedge (

) or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of Formula I maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included.For example, unless stated otherwise, it is intended that the compoundsof Formula I can exist as enantiomers and diastereomers or as racematesand mixtures thereof. The use of a solid line to depict bonds to one ormore asymmetric carbon atoms in a compound of Formula I and the use of asolid or dotted wedge to depict bonds to other asymmetric carbon atomsin the same compound is meant to indicate that a mixture ofdiastereomers is present.

In some embodiments, the compounds of Formula I (including saltsthereof) may exist in and/or be isolated as atropisomers (e.g., one ormore atropenantiomers). Those skilled in the art would recognize thatatropisomerism may exist in a compound that has two or more aromaticrings (for example, two aromatic rings linked through a single bond).See e.g., Freedman, T. B. et al., Absolute Configuration Determinationof Chiral Molecules in the Solution State Using Vibrational CircularDichroism. Chirality 2003, 15, 743-758; and Bringmann, G. et al.,Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew.Chem., Int. Ed. 2005, 44, 5384-5427.

When any racemate crystallizes, crystals of different types arepossible. One type is the racemic compound (true racemate) wherein onehomogeneous form of crystal is produced containing both enantiomers inequimolar amounts. Another type is a racemic mixture or conglomeratewherein two forms of crystal are produced in equal or different molaramounts each comprising a single enantiomer.

The compounds of Formula I (including salts thereof) may exhibit thephenomena of tautomerism and structural isomerism. For example, thecompounds of Formula I may exist in several tautomeric forms, includingthe enol and imine form, the amide and imidic acid form, and the ketoand enamine form and geometric isomers and mixtures thereof. All suchtautomeric forms are included within the scope of the compounds ofFormula I. Tautomers may exist as mixtures of a tautomeric set insolution. In solid form, usually one tautomer predominates. Even thoughone tautomer may be described, the present invention includes alltautomers of the compounds of Formula I. For example, when one of thefollowing two tautomers of the invention is disclosed in theexperimental section herein, those skilled in the art would readilyrecognize that the invention also includes the other.

For another example, when one of the following three tautomers of theinvention is disclosed in the experimental section herein, those skilledin the art would readily recognize that the invention also includesother tautomers such as the other two shown below.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of Formula I (including salts thereof)wherein one or more atoms are replaced by atoms having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention (including salts thereof) include isotopes of hydrogen, suchas ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of Formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e., ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron-emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I (including salts thereof)can generally be prepared by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

The present invention also provides compositions (e.g., pharmaceuticalcompositions) comprising a novel compound of Formula I (including apharmaceutically acceptable salt thereof) in the second aspect of theinvention. Accordingly, in one embodiment, the invention provides apharmaceutical composition comprising (a therapeutically effectiveamount of) a novel compound of Formula I (or a pharmaceuticallyacceptable salt thereof) and optionally comprising a pharmaceuticallyacceptable carrier. In one further embodiment, the invention provides apharmaceutical composition comprising (a therapeutically effectiveamount of) a compound of Formula I (or a pharmaceutically acceptablesalt thereof), optionally comprising a pharmaceutically acceptablecarrier and, optionally, at least one additional medicinal orpharmaceutical agent (such as an antipsychotic agent oranti-schizophrenia agent described below). In one embodiment, theadditional medicinal or pharmaceutical agent is an anti-schizophreniaagent as described below.

The pharmaceutically acceptable carrier may comprise any conventionalpharmaceutical carrier or excipient. Suitable pharmaceutical carriersinclude inert diluents or fillers, water and various organic solvents(such as hydrates and solvates). The pharmaceutical compositions may, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid, may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Non-limiting examples ofmaterials, therefore, include lactose or milk sugar and high molecularweight polyethylene glycols. When aqueous suspensions or elixirs aredesired for oral administration, the active compound therein may becombined with various sweetening or flavoring agents, coloring mattersor dyes and, if desired, emulsifying agents or suspending agents,together with diluents such as water, ethanol, propylene glycol,glycerin, or combinations thereof.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulation, solution or suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms may be suitably buffered, if desired.

The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. One of ordinary skill in theart would appreciate that the composition may be formulated insub-therapeutic dosage such that multiple doses are envisioned.

In one embodiment the composition comprises a therapeutically effectiveamount of a compound of Formula I (or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable carrier.

Compounds of Formula I (including pharmaceutically acceptable saltsthereof) are D1R modulators. In some embodiments, a compound of FormulaI is a D1R agonist [i.e., binding (having affinity for) and activatingD1R receptors]. In some embodiments, using dopamine as a reference fullD1R agonist, a compound of Formula I is a super agonist (i.e., acompound that is capable of producing a greater maximal response thanthe endogenous D1R agonist, dopamine, for a D1R receptor, and thusexhibiting an efficacy of more than about 100%, for example 120%). Insome embodiments, using dopamine as a reference full agonist, a compoundof Formula I is a full D1R agonist (i.e., having an efficacy of about100%, for example, 90%-100%, compared to that of dopamine). In someembodiments, using dopamine as a reference full D1R agonist, a compoundof Formula I is a partial agonist [i.e., a compound having only partialefficacy (i.e., less than 100%, for example 10%-80% or 50%-70%) at a D1receptor relative to the full agonist, dopamine, although it binds andactivates a D1 receptor]. A D1R agonist (including superagonist, fullagonist, and partial agonist) can agonize or partially agonize anactivity of D1R. In some embodiments, the EC₅₀ of a compound of FormulaI with respect to D1R is less than about 10 μM, 5 μM, 2 μM, 1 μM, 500nM, 200 nM, 100 nM, 50, 40, 30, 20, 10, 5, 2, or 1 nM.

As used herein, when referencing to a compound, the term “D1R modulator”or “D1R agonist” (including a super D1R agonist, a full D1R agonist, ora partial D1R agonist) refers to a compound that is a D1-like receptormodulator or a D1-like receptor agonist respectively (i.e., notnecessarily selective between/among subtypes of D1-like receptors). SeeLewis, JPET 286:345-353, 1998. D1Rs include, for example, D1 and D5 inhumans and D1A and D1B in rodents.

Administration of the compounds of Formula I may be effected by anymethod that enables delivery of the compounds to the site of action.These methods include, for example, enteral routes (e.g., oral routes,buccal routes, sublabial routes, sublingual routes), oral routes,intranasal routes, inhaled routes, intraduodenal routes, parenteralinjection (including intravenous, subcutaneous, intramuscular,intravascular or infusion), intrathecal routes, epidural routes,intracerebral routes, intracerbroventricular routes, topical, and rectaladministration.

In one embodiment of the present invention, the compounds of Formula Imay be administered/effected by oral routes.

Dosage regimens may be adjusted to provide the optimum desired response.For example, a single bolus may be administered, several divided dosesmay be administered over time or the dose may be proportionally reducedor increased as indicated by the exigencies of the therapeuticsituation. It may be advantageous to formulate parenteral compositionsin dosage unit form for ease of administration and uniformity of dosage.Dosage unit form, as used herein, refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active compound calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specifications for the dosage unitforms of the invention are dictated by a variety of factors such as theunique characteristics of the therapeutic agent and the particulartherapeutic or prophylactic effect to be achieved. In one embodiment ofthe present invention, the compounds of Formula I may be used to treathumans.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Forexample, doses may be adjusted based on pharmacokinetic orpharmacodynamic parameters, which may include clinical effects such astoxic effects and/or laboratory values. Thus, the present inventionencompasses intra-patient dose-escalation as determined by the skilledartisan. Determining appropriate dosages and regimens for administrationof the chemotherapeutic agent is well-known in the relevant art andwould be understood to be encompassed by the skilled artisan onceprovided the teachings disclosed herein.

The amount of the compound of Formula I or a pharmaceutically acceptablesalt thereof administered will be dependent on the subject beingtreated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. Generally, an effective dosage is in therange of about 0.0001 to about 50 mg per kg body weight per day, forexample about 0.01 to about 10 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.007 mg to about 3500mg/day, for example about 0.7 mg to about 700 mg/day. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

As used herein, the term “combination therapy” refers to theadministration of a compound of Formula I or a pharmaceuticallyacceptable salt thereof together with an at least one additionalpharmaceutical or medicinal agent (e.g., an anti-schizophrenia agent),either sequentially or simultaneously.

The present invention includes the use of a combination of a compound ofFormula I (or a pharmaceutically acceptable salt thereof) and one ormore additional pharmaceutically active agent(s). If a combination ofactive agents is administered, then they may be administeredsequentially or simultaneously, in separate dosage forms or combined ina single dosage form. Accordingly, the present invention also includespharmaceutical compositions comprising an amount of: (a) a first agentcomprising a compound of Formula I (including an N-oxide thereof or apharmaceutically acceptable salt of the compound or the N-oxide); (b) asecond pharmaceutically active agent; and (c) a pharmaceuticallyacceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of Formula I (including orpharmaceutically acceptable salts thereof), depending on the disease,disorder, or condition to be treated. Pharmaceutically active agentsthat may be used in combination with the compositions of the presentinvention include, without limitation:

(i) acetylcholinesterase inhibitors such as donepezil hydrochloride(ARICEPT, MEMAC); or Adenosine A_(2A) receptor antagonists such asPreladenant (SCH 420814) or SCH 412348;(ii) amyloid-β (or fragments thereof), such as Aβ₁₋₁₅ to pan HLADR-binding epitope (PADRE) and ACC-001 (Elan/Wyeth);(iii) antibodies to amyloid-β (or fragments thereof), such asbapineuzumab (also known as AAB-001) and AAB-002 (Wyeth/Elan);(iv) amyloid-lowering or -inhibiting agents (including those that reduceamyloid production, accumulation and fibrillization) such as colostrininand bisnorcymserine (also known as BNC);(v) alpha-adrenergic receptor agonists such as clonidine (CATAPRES);(vi) beta-adrenergic receptor blocking agents (beta blockers) such ascarteolol;(vii) anticholinergics such as amitriptyline (ELAVIL, ENDEP);(viii) anticonvulsants such as carbamazepine (TEGRETOL, CARBATROL);(ix) antipsychotics, such as lurasidone (also known as SM-13496;Dainippon Sumitomo);(x) calcium channel blockers such as nilvadipine (ESCOR, NIVADIL);(xi) catechol O-methyltransferase (COMT) inhibitors such as tolcapone(TASMAR);(xii) central nervous system stimulants such as caffeine;(xiii) corticosteroids such as prednisone (STERAPRED, DELTASONE);(xiv) dopamine receptor agonists such as apomorphine (APOKYN);(xv) dopamine receptor antagonists such as tetrabenazine (NITOMAN,XENAZINE, dopamine D2 antagonist such as Quetiapine);(xvi) dopamine reuptake inhibitors such as nomifensine maleate(MERITAL);(xvii) gamma-aminobutyric acid (GABA) receptor agonists such as baclofen(LIORESAL, KEMSTRO);(xviii) histamine 3 (H₃) antagonists such as ciproxifan;(xix) immunomodulators such as glatiramer acetate (also known ascopolymer-1; COPAXONE);(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX);(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) andinterferon beta-1b (BETASERON, BETAFERON);(xxii) levodopa (or its methyl or ethyl ester), alone or in combinationwith a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV,PARCOPA));(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists such asmemantine (NAMENDA, AXURA, EBIXA);(xxiv) monoamine oxidase (MAO) inhibitors such as selegiline (EMSAM);(xxv) muscarinic receptor (particularly M1 subtype) agonists such asbethanechol chloride (DUVOID, URECHOLINE);(xxvi) neuroprotective drugs such as2,3,4,9-tetrahydro-1H-carbazol-3-one oxime;(xxvii) nicotinic receptor agonists such as epibatidine;(xxviii) norepinephrine (noradrenaline) reuptake inhibitors such asatomoxetine (STRATTERA);(xxix) phosphodiesterase (PDE) inhibitors, for example, PDE9 inhibitorssuch as BAY 73-6691 (Bayer AG) and PDE 10 (e.g. PDE10A) inhibitors suchas papaverine;(xxx) other PDE inhibitors including (a) PDE1 inhibitors (e.g.,vinpocetine), (b) PDE2 inhibitors (e.g.,erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), (c) PDE4 inhibitors (e.g.,rolipram), and (d) PDE5 inhibitors (e.g., sildenafil (VIAGRA, REVATIO));(xxxi) quinolines such as quinine (including its hydrochloride,dihydrochloride, sulfate, bisulfate and gluconate salts);(xxxii) β-secretase inhibitors such as WY-25105;(xxxiii) γ-secretase inhibitors such as LY-411575 (Lilly);(xxxiv) serotonin (5-hydroxytryptamine) 1A (5-HT_(1A)) receptorantagonists such as spiperone;(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT₄) receptor agonists suchas PRX-03140 (Epix);(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonistssuch as mianserin (TORVOL, BOLVIDON, NORVAL);(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate,citalopram (CELEXA, CIPRAMIL);(xxxviii) trophic factors, such as nerve growth factor (NGF), basicfibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3),cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin,meteorin, and glial-derived neurotrophic factor (GDNF), and agents thatstimulate production of trophic factors, such as propentofylline;and the like.

The compound of Formula I (including a pharmaceutically acceptable saltthereof) is optionally used in combination with another active agent.Such an active agent may be, for example, an atypical antipsychotic oran anti-Parkinson's disease agent or an anti-Alzheimer's agent.Accordingly, another embodiment of the invention provides methods oftreating a D1-mediated disorder (e.g., a neurological and psychiatricdisorder associated with D1), comprising administering to a mammal aneffective amount of a compound of Formula I (including an N-oxidethereof or a pharmaceutically acceptable salt of the compound or theN-oxide) and further comprising administering another active agent.

As used herein, the term “another active agent” refers to anytherapeutic agent, other than the compound of Formula I (including or apharmaceutically acceptable salt thereof) that is useful for thetreatment of a subject disorder. Examples of additional therapeuticagents include antidepressants, antipsychotics (such asanti-schizophrenia), anti-pain, anti-Parkinson's disease agents,anti-LID (levodopa-induced dyskinesia), anti-Alzheimer's andanti-anxiety agents. Examples of particular classes of antidepressantsthat can be used in combination with the compounds of the inventioninclude norepinephrine reuptake inhibitors, selective serotonin reuptakeinhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidaseinhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs),serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropinreleasing factor (CRF) antagonists, α-adrenoreceptor antagonists, andatypical antidepressants. Suitable norepinephrine reuptake inhibitorsinclude tertiary amine tricyclics and secondary amine tricyclics.Examples of suitable tertiary amine tricyclics and secondary aminetricyclics include amitriptyline, clomipramine, doxepin, imipramine,trimipramine, dothiepin, butriptyline, iprindole, lofepramine,nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.Examples of suitable selective serotonin reuptake inhibitors includefluoxetine, fluvoxamine, paroxetine, and sertraline. Examples ofmonoamine oxidase inhibitors include isocarboxazid, phenelzine, andtranylcyclopramine. Examples of suitable reversible inhibitors ofmonoamine oxidase include moclobemide. Examples of suitable serotoninand noradrenaline reuptake inhibitors of use in the present inventioninclude venlafaxine. Examples of suitable atypical anti-depressantsinclude bupropion, lithium, nefazodone, trazodone and viloxazine.Examples of anti-Alzheimer's agents include Dimebon, NMDA receptorantagonists such as memantine; and cholinesterase inhibitors such asdonepezil and galantamine. Examples of suitable classes of anti-anxietyagents that can be used in combination with the compounds of theinvention include benzodiazepines and serotonin 1A (5-HT1A) agonists orantagonists, especially 5-HT1A partial agonists, and corticotropinreleasing factor (CRF) antagonists. Suitable benzodiazepines includealprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1A receptoragonists or antagonists include buspirone, flesinoxan, gepirone, andipsapirone. Suitable atypical antipsychotics include paliperidone,bifeprunox, ziprasidone, risperidone, aripiprazole, olanzapine, andquetiapine. Suitable nicotine acetylcholine agonists includeispronicline, varenicline and MEM 3454. Anti-pain agents includepregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam,ketamine and ziconotide. Examples of suitable anti-Parkinson's diseaseagents include L-DOPA (or its methyl or ethyl ester), a DOPAdecarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA),an Adenosine A_(2A) receptor antagonist [e.g., Preladenant (SCH 420814)or SCH 412348], benserazide (MADOPAR), α-methyldopa,monofluoromethyldopa, difluoromethyldopa, brocresine, orm-hydroxybenzylhydrazine), a dopamine agonist [such as apomorphine(APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX),dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride(DOPERGIN), pergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL),pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine(NEUPRO), SKF-82958 (GlaxoSmithKline), and sarizotan], a monoamineoxidase (MAO) inhibitor [such as selegiline (EMSAM), selegilinehydrochloride (L-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegilene,brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide(AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN),nialamide (NIAMID), rasagiline (AZILECT), iproniazide (MARSILID,IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide,toloxatone (HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (alsoknown as telepathine or banasterine), harmaline, linezolid (ZYVOX,ZYVOXID), and pargyline (EUDATIN, SUPIRDYL)], a catecholO-methyltransferase (COMT) inhibitor [such as tolcapone (TASMAR),entacapone (COMTAN), and tropolone], an N-methyl-D-aspartate (NMDA)receptor antagonist [such as amantadine (SYMMETREL)], anticholinergics[such as am itriptyline (ELAVIL, ENDEP), butriptyline, benztropinemesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine(BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN),scopolamine (TRANSDERM-SCOP), scopolamine methylbromide (PARMINE),dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE, tolterodine(DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienatebromide, propantheline (PRO-BANTHINE), cyclizine, imipraminehydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine,desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine(SURMONTIL), and glycopyrrolate (ROBINUL)], or a combination thereof.Examples of anti-schizophrenia agents include ziprasidone, risperidone,olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, oriloperidone. Some additional “another active agent” examples includerivastigmine (Exelon), Clozapine, Levodopa, Rotigotine, Aricept,Methylphenidate, memantine. milnacipran, guanfacine, bupropion, andatomoxetine.

As noted above, the compounds of Formula I (including pharmaceuticallyacceptable salts thereof) may be used in combination with one or moreadditional anti-schizophrenia agents which are described herein. When acombination therapy is used, the one or more additionalanti-schizophrenia agents may be administered sequentially orsimultaneously with the compound of the invention. In one embodiment,the additional anti-schizophrenia agent is administered to a mammal(e.g., a human) prior to administration of the compound of theinvention. In another embodiment, the additional anti-schizophreniaagent is administered to the mammal after administration of the compoundof the invention. In another embodiment, the additionalanti-schizophrenia agent is administered to the mammal (e.g., a human)simultaneously with the administration of the compound of the invention(or an N-oxide thereof or a pharmaceutically acceptable salt of theforegoing).

The invention also provides a pharmaceutical composition for thetreatment of schizophrenia in a mammal, including a human, whichcomprises an amount of a compound of Formula I (or a pharmaceuticallyacceptable salt thereof), as defined above (including hydrates, solvatesand polymorphs of said compound or pharmaceutically acceptable saltsthereof), in combination with one or more (for example one to three)anti-schizophrenia agents such as ziprasidone, risperidone, olanzapine,quetiapine, aripiprazole, asenapine, blonanserin, or iloperidone,wherein the amounts of the active agent and the combination when takenas a whole are therapeutically effective for treating schizophrenia.

The invention also provides a pharmaceutical composition for thetreatment of Parkinson's disease in a mammal (including cognitionimpairment associated with PD), including a human, which comprises anamount of a compound of Formula I (or a pharmaceutically acceptable saltthereof), as defined above (including hydrates, solvates and polymorphsof said compound or pharmaceutically acceptable salts thereof), incombination with one or more (for example one to three) anti-Parkinson'sdisease agents such as L-DOPA, wherein the amounts of the active agentand the combination when taken as a whole are therapeutically effectivefor treating Parkinson's disease.

It will be understood that the compounds of Formula I depicted above arenot limited to a particular stereoisomer (e.g. enantiomer oratropisomer) shown, but also include all stereoisomers and mixturesthereof.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the invention, including N-oxides and salts of thecompounds or N-oxides, can be prepared using known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents, which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures that can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high-performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

Compounds of Formula I and intermediates thereof may be preparedaccording to the following reaction schemes and accompanying discussion.Unless otherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, L¹, X¹, X², X³, X⁴, Q¹, and structural Formula I in the reactionschemes and discussion that follow are as defined above. In general, thecompounds of this invention may be made by processes which includeprocesses analogous to those known in the chemical arts, particularly inlight of the description contained herein. Certain processes for themanufacture of the compounds of this invention and intermediates thereofare provided as further features of the invention and are illustrated bythe following reaction schemes. Other processes are described in theexperimental section. The schemes and examples provided herein(including the corresponding description) are for illustration only, andnot intended to limit the scope of the present invention.

Scheme 1 refers to preparation of compounds of Formula I. Referring toScheme 1, compounds of Formula 1-1 [where Lg¹ is a suitable leavinggroup such as halo (e.g., F, Cl or Br)] and 1-2 [wherein Z¹ can be,e.g., halogen (e.g., Br or I) or trifluoromethanesulfonate (triflate)]are commercially available or can be made by methods described herein orother methods well known to those skilled in the art. A compound ofFormula 1-3 can be prepared by coupling a compound of Formula 1-1 with acompound of Formula 1-2 under suitable conditions. The coupling can beaccomplished, for example, by heating a mixture of a compound of Formula1-1 with a compound of Formula 1-2 in the presence of a base, such asCs₂CO₃, in an appropriate solvent, such as dimethyl sulfoxide (DMSO).Alternatively, a metal-catalyzed (such as using a palladium or coppercatalyst) coupling may be employed to accomplish the aforesaid coupling.In this variant of the coupling, a mixture of a compound of Formula 1-1and a compound of Formula 1-2 can be heated in the presence of a base(such as Cs₂CO₃), a metal catalyst [such as a palladium catalyst, e.g.,Pd(OAc)₂], and a ligand [such as1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (BINAP)] in anappropriate solvent, such as 1,4-dioxane. A compound of Formula 1-3 cansubsequently be reacted with a compound of Formula Q¹-Z² [wherein Z² canbe Br; B(OH)₂; B(OR)₂ wherein each R is independently H or C₁₋₆ alkyl,or wherein the two (OR) groups, together with the B atom to which theyare attached, form a 5- to 10-membered heterocycloalkyl optionallysubstituted with one or more C₁₋₆ alkyl; a trialkyltin moiety; or thelike] by a metal-catalyzed (such as using a palladium catalyst) couplingreaction to obtain a compound of Formula I. Compounds of Formula Q¹-Z²are commercially available or can be made by methods described herein orby methods analogous to those described in the chemical art.Alternatively, a compound of Formula 1-3 can be converted to a compoundof Formula 1-4 (wherein Z² is defined as above). For example, a compoundof Formula 1-3 (wherein Z¹ is halogen such as Br or I) can be convertedto a compound of Formula 1-4 [wherein Z² is B(OH)₂; B(OR)₂ wherein eachR is independently H or C₁₋₆ alkyl, or wherein the two (OR) groups,together with the B atom to which they are attached, form a 5- to10-membered heterocycloalkyl or heteroaryl optionally substituted withone or more C₁₋₆ alkyl] by methods described herein or other methodswell known to those skilled in the art. In this example, this reactioncan be accomplished, for example, by reacting a compound of Formula 1-3(wherein Z¹ is halogen such as Br) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane, a suitablebase (such as potassium acetate), and a palladium catalyst {such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)} in asuitable solvent such as 1,4-dioxane. In another example, a compound ofFormula 1-3 (wherein Z¹ is halogen such as Br) can be converted to acompound of Formula 1-4 (wherein Z² is a trialkyltin moiety) byalternate methods described herein or other methods well known to thoseskilled in the art. In this example, this reaction can be accomplished,for example, by reacting a compound of Formula 1-3 (wherein Z¹ ishalogen such as Br) with a hexaalkyldistannane (such ashexamethyldistannane) in the presence of a palladium catalyst [such astetrakis(triphenylphosphine)palladium(0)] in a suitable solvent such as1,4-dioxane. A compound of Formula 1-4 can then be reacted with acompound of Formula Q¹-Z¹ (wherein Z¹ is defined as above) by ametal-catalyzed (such as using a palladium catalyst) coupling reactionto obtain a compound of Formula I. Compounds of Formula Q¹-Z¹ arecommercially available or can be made by methods described herein or bymethods analogous to those described in the chemical art. The type ofreaction employed depends on the selection of Z¹ and Z². For example,when Z¹ is halogen or triflate and the Q¹-Z² reagent is a boronic acidor boronic ester, a Suzuki reaction may be used [A. Suzuki, J.Organomet. Chem. 1999, 576, 147-168; N. Miyaura and A. Suzuki, Chem.Rev. 1995, 95, 2457-2483; A. F. Littke et al., J. Am. Chem. Soc. 2000,122, 4020-4028]. In some specific embodiments, an aromatic iodide,bromide, or triflate of Formula 1-3 is combined with an aryl orheteroaryl boronic acid or boronic ester of Formula Q¹-Z² and a suitablebase, such as potassium phosphate, in a suitable organic solvent such astetrahydrofuran (THF). A palladium catalyst is added, such as S-Phosprecatalyst {also known aschloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)-tert-butylmethyl ether adduct}, and the reaction mixture is heated. Alternatively,when Z¹ is halogen or triflate and Z² is trialkyltin, a Stille couplingmay be employed [V. Farina et al., Organic Reactions 1997, 50, 1-652].More specifically, a compound of Formula 1-3 (wherein Z¹ is Br, I, ortriflate) may be combined with a compound of Formula Q¹-Z² (wherein theQ¹-Z² compound is a Q¹-stannane compound) in the presence of a palladiumcatalyst, such as dichlorobis(triphenylphosphine)palladium(II), in asuitable organic solvent such as toluene, and the reaction may beheated. Where Z¹ is Br, I, or triflate and Z² is Br or I, a Negishicoupling may be used [E. Erdik, Tetrahedron 1992, 48, 9577-9648]. Morespecifically, a compound of Formula 1-3 (wherein Z¹ is Br, I, ortriflate) may be transmetallated by treatment with 1 to 1.1 equivalentsof an alkyllithium reagent followed by a solution of 1.2 to 1.4equivalents of zinc chloride in an appropriate solvent such as THF at atemperature ranging from −80° C. to −65° C. After warming to atemperature between 10° C. and 30° C., the reaction mixture may betreated with a compound of Formula Q¹-Z² (wherein Z² is Br or I), andheated at 50° C. to 70° C. with addition of a catalyst such astetrakis(triphenylphosphine)palladium(0). The reaction may be carriedout for times ranging from 1 to 24 hours to yield the compound ofFormula I.

Scheme 2 also refers to preparation of compounds of Formula I. Referringto Scheme 2, compounds of Formula I may be prepared utilizing analogouschemical transformations to those described in Scheme 1, but with adifferent ordering of steps. Compounds of Formula 2-1 [wherein Pg¹ is asuitable protecting group such as Boc or Cbz when L¹ is NH or methyl,benzyl, tetrahydropyranyl (THP), or tert-butyldimethyl (TBS) when L¹ isO] are commercially available or can be made by methods described hereinor other methods well known to those skilled in the art. A compound ofFormula 2-1 can be converted to a compound of Formula 2-2 eitherdirectly or after conversion to a compound of Formula 2-3 using methodsanalogous to those described in Scheme 1. A compound of Formula 2-2 maythen be deprotected, using appropriate conditions depending on theselection of the Pg¹ group, to obtain a compound of Formula 2-4, whichin turn can be coupled with a compound of Formula 1-1 in Scheme 1 toafford a compound of Formula I. The coupling conditions employed may beanalogous to those described for the preparation of a compound ofFormula 1-3 in Scheme 1.

Scheme 3 refers to a preparation of a compound of Formula 3-6 wherein A¹is a moiety of Formula A^(1a) or a Pg¹. Referring to Scheme 3, compoundsof Formula 3-1 are commercially available or can be made by methodsdescribed herein or other methods well known to those skilled in theart. A compound of Formula 3-3 can be prepared by reacting compound ofFormula 3-1 with acylated enol of Formula 3-2 in the presence of asuitable palladium catalyst such as palladium(II) acetate,tributylmethoxystannane and a suitable phosphine ligand (such astri-o-tolylphosphine). The resulting aryl ketone of Formula 3-3 can beconverted to the diketone of Formula 3-4 upon treatment with a suitableoxidizing agent such as selenium dioxide. Diketones of Formula 3-4 canbe reacted with glycinamide or a salt thereof (such as an acetic acidsalt) in the presence of a base such as sodium hydroxide to obtainpyrazinones of Formula 3-5. Alkylation of the pyrazinone nitrogen toobtain a compound of Formula 3-6 can be achieved by treatment of acompound of Formula 3-5 with a base [such as lithium diisopropylamide(LDA), lithium bis(trimethylsilyl)amide (LHMDS), and the like] and acompound of the formula R¹¹—Z³ [wherein Z³ is an acceptable leavinggroup such as Cl, Br, I, methanesulfonate (mesylate), and the like andwherein R¹¹ is for example C₁₋₃ alkyl (e.g., methyl)]. Suitable reactionsolvents typically can be selected from polar aprotic solvents such asN,N-dimethylformamide (DMF), 1,4-dioxane, or THF.

Alternatively, a compound of Formula 3-6 may be prepared as in Scheme 4wherein L¹ is O, NH, N(C₁₋₄ alkyl) and N(C₃₋₆ cycloalkyl). Referring toScheme 4, compounds of Formula 4-1 and 4-2 are commercially available orcan be made by methods described herein or other methods well known tothose skilled in the art. A compound of Formula 4-3 can be prepared bycoupling a compound of Formula 4-1 with a compound of Formula 4-2. Theaforesaid coupling may be accomplished by reacting a compound of Formula4-1 with a compound of Formula 4-2 in the presence of a suitable base(such as potassium carbonate), a suitable catalyst [such astetrakis(triphenylphosphine)palladium(0)], and a suitable solvent (suchas ethanol). A compound of Formula 4-3 can be reacted with maleicanhydride and hydrogen peroxide in a solvent (such as dichloromethane)to provide a compound of Formula 4-4, which may contain a mixture ofN-oxide regioisomers. A compound of Formula 4-5 can be prepared from acompound of Formula 4-4 by heating with acetic anydride; the initialproduct can be saponified using a base (such as NaOH) in a suitablepolar solvent (such as water or methanol). A compound of Formula 3-6 canbe prepared from a compound of Formula 4-5 by reaction with a suitablebase (such as LDA, LHMDS and the like), lithium bromide, and a compoundof the formula R¹¹—Z³ (wherein Z³ is an acceptable leaving group such asCl, Br, I, mesylate, and the like). Suitable reaction solvents typicallycan be selected from polar aprotic solvents (such as DMF, 1,4-dioxane,or THF).

Scheme 5 refers to a preparation of a compound of Formula 5-4 wherein L¹is O, NH, carbonyl, N(C₁₋₄ alkyl) and N(C₃₋₆ cycloalkyl) and A¹ is amoiety of Formula A^(1a), or a Pg² (such as a benzyl group). Referringto Scheme 5, compounds of Formula 4-1 and 5-1 are commercially availableor can be made by methods described herein or other methods well knownto those skilled in the art. A compound of Formula 5-2 can be preparedby coupling a compound of Formula 4-1 with an enoltrifluoromethanesulfonate of Formula 5-1. The aforesaid coupling may beaccomplished by reacting a compound of Formula 4-1 with atrifluoromethanesulfonate of Formula 5-1 in the presence of a suitablebase (such as potassium carbonate or sodium carbonate), a suitablecatalyst [such as palladium(II) acetate], optionally a suitable ligand(such as tricyclohexylphosphine), and optionally a suitablephase-transfer catalyst such as tetrabutylammonium chloride. Suitablereaction solvents typically can be selected from polar aprotic solventssuch as 1,4-dioxane or THF. A compound of Formula 5-2 can be reactedwith 1 to 5 equivalents of a suitable base [such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)] under an oxygen atmosphere toobtain a compound of Formula 5-3. Suitable reaction solvents typicallycan be selected from polar aprotic solvents such as DMF, 1,4-dioxane, orTHF. A compound of Formula 5-4 can be obtained by reacting a compound ofFormula 5-3 with hydrazine in a suitable solvent such as 1-butanol.

Scheme 6 refers to a preparation of a compound of Formula 6-5. Referringto Scheme 6, a compound of Formula 6-1 can be prepared as described inScheme 5, wherein Pg² is a suitable protecting group (such as benzyl). Acompound of Formula 6-1 can be converted to a suitably protectedcompound of Formula 6-2 using methods described herein or other methodswell known to those skilled in the art, wherein Pg³ is a suitableprotecting group (such as THP) that can be removed under orthogonalreaction conditions to Pg². A compound of Formula 6-3 can be prepared byselective removal of Pg² under suitable deprotection conditionsdepending on the selection of Pg². For example, when Pg² is a benzylgroup, it can be removed by treatment with palladium (10% on carbon)under hydrogenation condition in a suitable solvent, such as methanoland ethyl acetate. Using the aforementioned reaction conditionsdescribed in Scheme 1, a compound of Formula 6-3 can be coupled with areagent of Formula 1-1 to yield a compound of Formula 6-4. A compound ofFormula 6-5 can be obtained by removing Pg³ under suitable deprotectionconditions depending on the selection of Pg³. For example, when Pg³ isTHP, it can be removed under acidic conditions, such as hydrogenchloride in a suitable solvent, such as dichloromethane.

Scheme 7 refers to a preparation of a compound of Formula 7-6 [whereinR⁹ is, for example, C₁₋₃ alkyl (e.g., methyl); R¹¹ is, for example, H orC₁₋₃ alkyl (e.g., methyl); and Pg⁴ is a suitable protecting group [e.g.,2-(trimethylsilyl)ethoxymethyl (SEM), tert-butoxycarbonyl (Boc), orbenzyloxymethyl acetal (BOM)]. Referring to Scheme 7, compounds ofFormula 7-1 and 7-2 are commercially available or can be prepared bymethods described herein or other methods well known to those skilled inthe art. A compound of Formula 7-3 can be prepared by coupling acompound of Formula 7-1 with a compound of Formula 7-2, in the presenceof a suitable base (such as potassium carbonate) and a suitable catalyst{such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)}. Acompound of Formula 7-4 can be prepared by selective removal of Pg²under suitable de-protection conditions depending on the selection ofPg². For example, when Pg² is a benzyl group, it can be removed bytreatment with palladium (10% on carbon) under hydrogenation conditionin a suitable solvent, such as methanol and ethyl acetate. Using theaforementioned reaction conditions described in Scheme 1, a compound ofFormula 7-4 can be coupled with a reagent of Formula 1-1 to yield acompound of Formula 7-5. Alternatively, a compound of Formula 7-5 can beprepared from intermediate 1-4, following the coupling conditionsdescribed in Scheme 1. A compound of Formula 7-6 can then be obtainedfrom a compound of Formula 7-5 by removing Pg⁴ under suitabledeprotection conditions that are known to those skilled in the art.

Scheme 8 refers to preparation of compounds of Formula 8-5 and 8-6.Referring to Scheme 8, compounds of Formula 8-1 are commerciallyavailable or can be made by methods described herein or other methodswell known to those skilled in the art. A compound of Formula 8-1 can beconverted to a compound of Formula 8-2 either directly or afterconversion to a compound of Formula 8-3 using methods analogous to thosedescribed in Scheme 1. The nitro group of a compound of Formula 8-2 canthen be converted to an amine via hydrogenation in the presence of asuitable catalyst, such as palladium (10% on carbon), to yield acompound of Formula 8-4. A compound of Formula 8-4 can then be coupledwith a compound of Formula 1-1 in Scheme 1 to afford a compound ofFormula 8-5. The coupling conditions employed may be analogous to thosedescribed for the preparation of a compound of Formula 1-3 in Scheme 1.A compound of Formula 8-6 can be prepared via N-alkylation of a compoundof formula 8-5 using a reagent of Y—Z³, wherein Y is C₁₋₄ alkyl, or C₃₋₆cycloalkyl, and Z³ is an acceptable leaving group such as Cl, Br, I,mesylate, and the like.

Scheme 9 refers to preparation of compounds of Formula 9-4. Referring toScheme 9, a compound of Formula 9-1 can be prepared via triflation of acompound of Formula 2-4 (Scheme 2) using a suitable reagent such astrifluoromethanesulfonic anhydride in the presence of a suitable basesuch as triethylamine. A compound of Formula 9-1 can be converted to acompound of Formula 9-2 by coupling with potassium thioacetate, in thepresence of a suitable metal catalyst, such astris(dibenzylideneacetone)dipalladium(0), and a suitable ligand, such as(R)-(−)-1-[(S_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,in a suitable solvent, such as toluene. A compound of Formula 9-2 canthen be hydrolyzed to obtain a compound of Formula 9-3, which in turncan be coupled with a compound of Formula 1-1 in Scheme 1 to afford acompound of Formula 9-4. The coupling conditions employed may beanalogous to those described for the preparation of a compound ofFormula 1-3 in Scheme 1.

Scheme 10 refers to a preparation of a compound of Formula 10-3 [whereinA^(l) is either Pg² as defined above or a moiety of Formula A^(1a)],which can be used in Scheme 2 as intermediate/starting material for thepreparation of compounds of Formula I. Referring to Scheme 3, compoundsof Formula 10-1 are commercially available or can be made by methodsdescribed herein or other methods well known to those skilled in theart. A compound of Formula 10-1 can be reacted with4-chloro-3-nitropyridine and the initial product can be subsequentlyreduced to obtain a compound of Formula 10-2. Examples of suitablereaction conditions for the coupling of a compound of Formula 10-1 with4-chloro-3-nitropyridine include mixing the two reactants with asuitable base, such as triethylamine, in a suitable reaction solventsuch as ethanol. The subsequent reduction of the nitro group to afford acompound of Formula 10-2 can be achieved by, for example, hydrogenationin the presence of a catalyst such as palladium on carbon in a suitablesolvent such as methanol. Suitable hydrogen pressures for the aforesaidreaction are typically between 1 atm and 4 atm. A compound of Formula10-2 can then be heated with acetic anhydride and triethyl orthoformateto obtain a compound of Formula 10-3.

Scheme 11 refers to a preparation of a compound of Formula 11-2 [whereinR¹⁰ is H or C₁₋₃ alkyl, for example methyl], which is an example of acompound of Formula I. Referring to Scheme 11, a compound of Formula11-1 can be prepared by methods described in Scheme 1. A compound ofFormula 11-1 can be reacted with chloroacetaldehyde to obtain a compoundof Formula 11-2 typically at an elevated temperature for about 1 hour to24 hours.

Scheme 12 refers to a preparation of a compound of Formula 12-4.Referring to Scheme 12, compounds of Formula 12-1 are commerciallyavailable or can be made by methods described herein or other methodswell known to those skilled in the art. The free NH of a compound ofFormula 12-1 can be protected by a suitable amine protecting group Pg⁵such as 2-(trimethylsilyl)ethoxymethyl (SEM) to give a mixture ofregioisomers of Formula 12-2A and 12-2B. The mixture can be coupled withintermediate 2-4 under the conditions described in Scheme 1 to give amixture of compounds of Formula 12-3A and 12-3B, which upon deprotectionunder suitable reaction conditions depending on the choice of Pg⁵ yielda compound of Formula 12-4.

Additional starting materials and intermediates useful for making thecompounds of the present invention can be obtained from chemical vendorssuch as Sigma-Aldrich or can be made according to methods described inthe chemical art.

Those skilled in the art can recognize that in all of the Schemesdescribed herein, if there are functional (reactive) groups present on apart of the compound structure such as a substituent group, for exampleR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, L¹, X¹, X², X³, X⁴, andQ¹, etc., further modification can be made if appropriate and/ordesired, using methods well known to those skilled in the art. Forexample, a —CN group can be hydrolyzed to afford an amide group; acarboxylic acid can be converted to an amide; a carboxylic acid can beconverted to an ester, which in turn can be reduced to an alcohol, whichin turn can be further modified. For another example, an OH group can beconverted into a better leaving group such as a methanesulfonate, whichin turn is suitable for nucleophilic substitution, such as by a cyanideion (CN⁻). For another example, an —S— can be oxidized to —S(═O)— and/or—S(═O)₂—. For yet another example, an unsaturated bond such as C═C orC≡C can be reduced to a saturated bond by hydrogenation. In someembodiments, a primary amine or a secondary amine moiety (present on asubstituent group such as R³, R⁴, R⁹, R¹⁰, etc.) can be converted to anamide, sulfonamide, urea, or thiourea moiety by reacting it with anappropriate reagent such as an acid chloride, a sulfonyl chloride, anisocyanate, or a thioisocyanate compound. One skilled in the art willrecognize further such modifications. Thus, a compound of Formula Ihaving a substituent that contains a functional group can be convertedto another compound of Formula I having a different substituent group.

Similarly, those skilled in the art can also recognize that in all ofthe schemes described herein, if there are functional (reactive) groupspresent on a substituent group such as R³, R⁴, R⁹, R¹⁰, etc., thesefunctional groups can be protected/deprotected in the course of thesynthetic scheme described here, if appropriate and/or desired. Forexample, an OH group can be protected by a benzyl, methyl, or acetylgroup, which can be deprotected and converted back to the OH group in alater stage of the synthetic process. For another example, an NH₂ groupcan be protected by a benzyloxycarbonyl (Cbz) or Boc group; conversionback to the NH₂ group can be carried out at a later stage of thesynthetic process via deprotection.

As used herein, the term “reacting” (or “reaction” or “reacted”) refersto the bringing together of designated chemical reactants such that achemical transformation takes place generating a compound different fromany initially introduced into the system. Reactions can take place inthe presence or absence of solvent.

Compounds of Formula I may exist as stereoisomers, such as atropisomers,racemates, enantiomers, or diastereomers. Conventional techniques forthe preparation/isolation of individual enantiomers include chiralsynthesis from a suitable optically pure precursor or resolution of theracemate using, for example, chiral high-performance liquidchromatography (HPLC). Alternatively, the racemate (or a racemicprecursor) may be reacted with a suitable optically active compound, forexample, an alcohol, or, in the case where the compound contains anacidic or basic moiety, an acid or base such as tartaric acid or1-phenylethylamine. The resulting diastereomeric mixture may beseparated by chromatography and/or fractional crystallization and one orboth of the diastereoisomers converted to the corresponding pureenantiomer(s) by means well known to one skilled in the art. Chiralcompounds of Formula I (and chiral precursors thereof) may be obtainedin enantiomerically enriched form using chromatography, typically HPLC,on an asymmetric resin with a mobile phase consisting of a hydrocarbon,typically heptane or hexane, containing from 0% to 50% 2-propanol,typically from 2% to 20%, and from 0% to 5% of an alkylamine, typically0.1% diethylamine. Concentration of the eluate affords the enrichedmixture. Stereoisomeric conglomerates may be separated by conventionaltechniques known to those skilled in the art. See, e.g., Stereochemistryof Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York,1994), the disclosure of which is incorporated herein by reference inits entirety. Suitable stereoselective techniques are well known tothose of ordinary skill in the art.

Where a compound of Formula I contains an alkenyl or alkenylene(alkylidene) group, geometric cis/trans (or Z/E) isomers are possible.Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization. Salts of the present invention can be preparedaccording to methods known to those of skill in the art.

The compounds of Formula I that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate the compound of the present invention from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the basic compounds of this invention can be prepared by treating thebasic compound with a substantially equivalent amount of the selectedmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon evaporation of thesolvent, the desired solid salt is obtained. The desired acid salt canalso be precipitated from a solution of the free base in an organicsolvent by adding an appropriate mineral or organic acid to thesolution.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,isonicotinic acid, lactic acid, pantothenic acid, bitartric acid,ascorbic acid, 2,5-dihydroxybenzoic acid, gluconic acid, saccharic acid,formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, and pamoic [i.e.,4,4′-methanediylbis(3-hydroxynaphthalene-2-carboxylic acid)] acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such as ethanesulfonicacid, or the like.

Those compounds of Formula I that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline earth metalsalts, and particularly the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theacidic compounds of Formula I. These salts may be prepared by anysuitable method, for example, treatment of the free acid with aninorganic or organic base, such as an amine (primary, secondary ortertiary), an alkali metal hydroxide or alkaline earth metal hydroxide,or the like. These salts can also be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, for example under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are, for example, employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

Pharmaceutically acceptable salts of compounds of Formula I (includingcompounds of Formula Ia or Ib) may be prepared by one or more of threemethods:

(i) by reacting the compound of Formula I with the desired acid or base;(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of Formula I or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or(iii) by converting one salt of the compound of Formula I to another byreaction with an appropriate acid or base or by means of a suitable ionexchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionized to almost non-ionized.

Polymorphs can be prepared according to techniques well-known to thoseskilled in the art, for example, by crystallization.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture may havealmost identical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, New York, 1994).

The invention also includes isotopically labeled compounds of Formula Iwherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Isotopically labeled compoundsof Formula I (or pharmaceutically acceptable salts thereof or N-oxidesthereof) can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those describedherein, using an appropriate isotopically labeled reagent in place ofthe non-labeled reagent otherwise employed.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds ofFormula I with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

The compounds of Formula I should be assessed for theirbiopharmaceutical properties, such as solubility and solution stability(across pH), permeability, etc., in order to select the most appropriatedosage form and route of administration for treatment of the proposedindication.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term “excipient” is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention (or pharmaceutically acceptable salts thereof) andmethods for their preparation will be readily apparent to those skilledin the art. Such compositions and methods for their preparation may befound, for example, in Remington's Pharmaceutical Sciences, 19th Edition(Mack Publishing Company, 1995).

The compounds of the invention (including pharmaceutically acceptablesalts thereof and N-oxides thereof) may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid, semi-solidand liquid systems such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, or powders; lozenges (includingliquid-filled); chews; gels; fast dispersing dosage forms; films;ovules; sprays; and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsules(made, for example, from gelatin or hydroxypropyl methyl cellulose) andtypically comprise a carrier, for example, water, ethanol, polyethyleneglycol, propylene glycol, methyl cellulose, or a suitable oil, and oneor more emulsifying agents and/or suspending agents. Liquid formulationsmay also be prepared by the reconstitution of a solid, for example, froma sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described by Liang andChen, Expert Opinion in Therapeutic Patents 2001, 11, 981-986.

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinizedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, for example, from 5 weight % to 20weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulfate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, for example, from 0.5 weight% to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colorants, flavoringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt-congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound ofFormula I, a film-forming polymer, a binder, a solvent, a humectant, aplasticizer, a stabilizer or emulsifier, a viscosity-modifying agent anda solvent. Some components of the formulation may perform more than onefunction.

The compound of Formula I (or pharmaceutically acceptable salts thereofor N-oxides thereof) may be water-soluble or insoluble. A water-solublecompound typically comprises from 1 weight % to 80 weight %, moretypically from 20 weight % to 50 weight %, of the solutes. Less solublecompounds may comprise a smaller proportion of the composition,typically up to 30 weight % of the solutes. Alternatively, the compoundof Formula I may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavoringsand flavor enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Verma et al., PharmaceuticalTechnology On-line, 25(2), 1-14 (2001). The use of chewing gum toachieve controlled release is described in WO 00/35298.

The compounds of the invention (including pharmaceutically acceptablesalts thereof) may also be administered directly into the blood stream,into muscle, or into an internal organ. Suitable means for parenteraladministration include intravenous, intraarterial, intraperitoneal,intrathecal, intraventricular, intraurethral, intrasternal,intracranial, intramuscular, intrasynovial and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(for example to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilization, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of Formula I (including pharmaceuticallyacceptable salts thereof) used in the preparation of parenteralsolutions may be increased by the use of appropriate formulationtechniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as asuspension or as a solid, semi-solid, or thixotropic liquid foradministration as an implanted depot providing modified release of theactive compound. Examples of such formulations include drug-coatedstents and semi-solids and suspensions comprising drug-loadedpoly(DL-lactic-coglycolic acid) (PLGA) microspheres.

The compounds of the invention (including pharmaceutically acceptablesalts thereof) may also be administered topically, (intra)dermally, ortransdermally to the skin or mucosa. Typical formulations for thispurpose include gels, hydrogels, lotions, solutions, creams, ointments,dusting powders, dressings, foams, films, skin patches, wafers,implants, sponges, fibers, bandages and microemulsions. Liposomes mayalso be used. Typical carriers include alcohol, water, mineral oil,liquid petrolatum, white petrolatum, glycerin, polyethylene glycol andpropylene glycol. Penetration enhancers may be incorporated. See e.g.,Finnin and Morgan, J. Pharm. Sci. 1999, 88, 955-958.

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g., Powderject™, Bioject™, etc.)injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention (including pharmaceutically acceptablesalts thereof) can also be administered intranasally or by inhalation,typically in the form of a dry powder (either alone; as a mixture, forexample, in a dry blend with lactose; or as a mixed component particle,for example, mixed with phospholipids, such as phosphatidylcholine) froma dry powder inhaler, as an aerosol spray from a pressurized container,pump, spray, atomizer (for example an atomizer usingelectrohydrodynamics to produce a fine mist), or nebulizer, with orwithout the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or asnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilizing, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronized to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the compound of theinvention, a suitable powder base such as lactose or starch and aperformance modifier such as L-leucine, mannitol, or magnesium stearate.The lactose may be anhydrous or in the form of the monohydrate. Othersuitable excipients include dextran, glucose, maltose, sorbitol,xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μL to 100 μL. A typical formulation may comprisea compound of Formula I or a pharmaceutically acceptable salt thereof,propylene glycol, sterile water, ethanol and sodium chloride.Alternative solvents which may be used instead of propylene glycolinclude glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 0.01 to 100 mg of the compound ofFormula I. The overall daily dose will typically be in the range 1 μg to200 mg, which may be administered in a single dose or, more usually, asdivided doses throughout the day.

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

The compounds of the invention (including pharmaceutically acceptablesalts thereof) may also be administered directly to the eye or ear,typically in the form of drops of a micronized suspension or solution inisotonic, pH-adjusted, sterile saline. Other formulations suitable forocular and aural administration include ointments, gels, biodegradable(e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g.,silicone) implants, wafers, lenses and particulate or vesicular systems,such as niosomes or liposomes. A polymer such as crossed-linkedpolyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosicpolymer, for example, hydroxypropyl methyl cellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, forexample, gelan gum, may be incorporated together with a preservative,such as benzalkonium chloride. Such formulations may also be deliveredby iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

The compounds of the invention (including pharmaceutically acceptablesalts thereof) may be combined with soluble macromolecular entities,such as cyclodextrin and suitable derivatives thereof or polyethyleneglycol-containing polymers, in order to improve their solubility,dissolution rate, taste-masking, bioavailability and/or stability foruse in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e., as a carrier, diluent, or solubilizer. Most commonlyused for these purposes are alpha-, beta- and gamma-cyclodextrins,examples of which may be found in International Patent Applications Nos.WO 91/11172, WO 94/02518 and WO 98/55148.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof Formula I a prodrug thereof or a salt of such compound or prodrug anda second compound as described above. The kit comprises means forcontaining the separate compositions such as a container, a dividedbottle or a divided foil packet. Typically the kit comprises directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are for exampleadministered in different dosage forms (e.g., oral and parenteral), areadministered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a transparent plastic material.During the packaging process recesses are formed in the plastic foil.The recesses have the size and shape of the tablets or capsules to bepacked. Next, the tablets or capsules are placed in the recesses and thesheet of relatively stiff material is sealed against the plastic foil atthe face of the foil which is opposite from the direction in which therecesses were formed. As a result, the tablets or capsules are sealed inthe recesses between the plastic foil and the sheet. In someembodiments, the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Othervariations of memory aids will be readily apparent. A “daily dose” canbe a single tablet or capsule or several pills or capsules to be takenon a given day. Also, a daily dose of Formula I compound can consist ofone tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. For example, the dispenser is equipped with a memoryaid, so as to further facilitate compliance with the regimen. An exampleof such a memory aid is a mechanical counter which indicates the numberof daily doses that has been dispensed. Another example of such a memoryaid is a battery-powered micro-chip memory coupled with a liquid crystalreadout, or audible reminder signal which, for example, reads out thedate that the last daily dose has been taken and/or reminds one when thenext dose is to be taken.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters that can be changed or modified to yield essentially the sameresults. Additional compounds within the scope of this invention may beprepared using the methods illustrated in these Examples, either aloneor in combination with techniques generally known in the art. In thefollowing Examples and Preparations, “DMSO” means dimethyl sulfoxide,“N” where referring to concentration means Normal, “M” means molar, “mL”means milliliter, “mmol” means millimoles, “μmol” means micromoles,“eq.” means equivalent, “° C.” means degrees Celsius, “MHz” meansmegahertz, “HPLC” means high-performance liquid chromatography.

EXAMPLES

The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification. Anhydroussolvents were employed where appropriate, generally AcroSeal® productsfrom Acros Organics or DriSolv® products from EMD Chemicals. In othercases, commercial solvents were passed through columns packed with 4 Åmolecular sieves, until the following QC standards for water wereattained: a) <100 ppm for dichloromethane, toluene,N,N-dimethylformamide and tetrahydrofuran; b) <180 ppm for methanol,ethanol, 1,4-dioxane and diisopropylamine. For very sensitive reactions,solvents were further treated with metallic sodium, calcium hydride ormolecular sieves, and distilled just prior to use. Products weregenerally dried under vacuum before being carried on to furtherreactions or submitted for biological testing. Mass spectrometry data isreported from either liquid chromatography-mass spectrometry (LCMS),atmospheric pressure chemical ionization (APCI) or gaschromatography-mass spectrometry (GCMS) instrumentation. Chemical shiftsfor nuclear magnetic resonance (NMR) data are expressed in parts permillion (ppm, δ) referenced to residual peaks from the deuteratedsolvents employed. In some examples, chiral separations were carried outto separate enantiomers or atropisomers (or atropenantiomers) of certaincompounds of the invention (in some examples, the separated atropisomersare designated as ENT-1 and ENT-2, according to their order of elution).In some examples, the optical rotation of an enantiomer or atropisomerwas measured using a polarimeter. According to its observed rotationdata (or its specific rotation data), an enantiomer or atropisomer (oratropenantiomer) with a clockwise rotation was designated as the(+)-enantiomer or (+)-atropisomer [or the (+) atropenantiomer] and anenantiomer or atropisomer (or atropenantiomer) with a counter-clockwiserotation was designated as the (−)-enantiomer or (−)-atropisomer [or the(−) atropenantiomer].

Reactions proceeding through detectable intermediates were generallyfollowed by LCMS, and allowed to proceed to full conversion prior toaddition of subsequent reagents. For syntheses referencing procedures inother Examples or Methods, reaction conditions (reaction time andtemperature) may vary. In general, reactions were followed by thin layerchromatography or mass spectrometry, and subjected to work-up whenappropriate. Purifications may vary between experiments: in general,solvents and the solvent ratios used for eluents/gradients were chosento provide appropriate R_(f)s or retention times.

Example 14-[4-(4,6-Dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[2,3-d]pyrimidine(1)

Step 1. Synthesis of 2-aminofuran-3-carbonitrile (C1)

1,4-Dioxane-2,5-diol (hydroxyacetaldehyde dimer, 5 g, 40 mmol) wasdissolved in water (5 mL), treated with aqueous hydrochloric acid (0.1M, 15 mL), and allowed to stir for 18 hours. Malononitrile (4.72 mL,74.9 mmol) was added drop-wise, followed by the addition of diethylamine(7.72 mL, 74.9 mmol) drop-wise. The reaction mixture was stirred at roomtemperature for 3 hours and was then quenched with saturated aqueoussodium bicarbonate solution. The mixture was extracted with ethylacetate, and the combined organic layers were dried over magnesiumsulfate. After removal of solvent in vacuo, the residue was purified bysilica gel chromatography (Gradient: 20% to 40% ethyl acetate inheptane) to provide the product as a yellow solid. Yield: 3.22 g, 28mmol, 70%. LCMS m/z 108.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.72 (d,J=2.1 Hz, 1H), 6.29 (d, J=2.3 Hz, 1H), 4.72 (br s, 2H).

Step 2. Synthesis of furo[2,3-d]pyrimidin-4-amine (C2)

Compound C1 (100 mg, 0.925 mmol) was dissolved in formamide (2 mL) andthe reaction mixture was heated at 120° C. overnight. The reactionmixture was cooled to room temperature and partitioned between water andethyl acetate. The aqueous layer was extracted with ethyl acetate anddichloromethane. The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford the product as ayellow solid. Yield: 21 mg, 0.16 mmol, 17%. LCMS m/z 135.9 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 6.89 (d,J=2.5 Hz, 1H).

Step 3. Synthesis of 4-chlorofuro[2, 3-d]pyrimidine (C3)

A mixture of C2 (660 mg, 4.88 mmol), tent-butyl nitrite (12.1 mL, 97.7mmol), and trimethylsilyl chloride (3.12 mL, 24.4 mmol) in acetonitrile(20 mL) was stirred at 50° C. for 1 hour. The reaction was cooled toroom temperature and quenched with aqueous sodium hydroxide solution (2M, 30 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL),and the combined organic layers were dried over sodium sulfate. Thesolvent was removed in vacuo and the residue was purified viachromatography on silica gel (Gradient: 0% to 30% ethyl acetate inheptane) to provide the product as a volatile white solid. Yield: 168mg, 1.09 mmol, 22%. LCMS m/z 154.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.77 (s, 1H), 7.76 (d, J=0.8 Hz, 1H), 7.25 (d, J=0.8 Hz, 1H).

Step 4. Synthesis of 5-(4-methoxy-2-methylphenyl)-4,6-dimethylpyrimidine (C4)

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethanecomplex (5 g, 6 mmol) was added to a degassed mixture of2-(4-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30g, 120 mmol), 5-bromo-4,6-dimethylpyrimidine (22.5 g, 120 mmol), andpotassium phosphate (76.3 g, 359 mmol) in 1,4-dioxane (300 mL) and water(150 mL). The reaction mixture was heated at reflux for 4 hours,whereupon it was filtered and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: ethyl acetate in petroleum ether)provided the product as a brown solid. Yield: 25 g, 110 mmol, 92%. LCMSm/z 229.3 [M+Hl. ¹H NMR (300 MHz, CDCl₃) δ 8.95 (s, 1H), 6.94 (d, J=8.2Hz, 1H), 6.87-6.89 (m, 1H), 6.84 (dd, J=8.3, 2.5 Hz, 1H), 3.86 (s, 3H),2.21 (s, 6H), 1.99 (s, 3H).

Step 5. Synthesis of 4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol (C5)

Boron tribromide (3.8 mL, 40 mmol) was added drop-wise to a solution ofC4 (3.0 g, 13 mmol) in dichloromethane (150 mL) at −70° C. The reactionmixture was stirred at room temperature for 16 hours, then adjusted topH 8 with saturated aqueous sodium bicarbonate solution. The aqueouslayer was extracted with dichloromethane (3×200 mL), and the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography (Gradient: 60% to 90%ethyl acetate in petroleum ether) afforded the product as a yellowsolid. Yield: 1.2 g, 5.6 mmol, 43%. LCMS m/z 215.0 [M+Hl. ¹H NMR (400MHz, CDCl₃) δ 8.98 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.86 (d, J=2.3 Hz,1H), 6.80 (dd, J=8.3, 2.5 Hz, 1H), 2.24 (s, 6H), 1.96 (s, 3H).

Step 6. Synthesis of4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[2,3-d]pyrimidine(1)

To a stirred solution of C3 (33 mg, 0.21 mmol) in dimethyl sulfoxide (1mL) was added C5 (45 mg, 0.21 mmol) and cesium carbonate (205 mg, 0.63mmol). The reaction mixture was stirred at 120° C. for 3 hours, then wascooled to room temperature. The reaction mixture was partitioned betweenethyl acetate and water, and the aqueous layer was extracted twice withethyl acetate. The organic layers were combined and dried over magnesiumsulfate. The solvent was removed in vacuo and the residue was purifiedvia silica gel chromatography (Gradient: 0% to 40% [80:20:1dichloromethane/methanol/concentrated ammonium hydroxide] indichloromethane) to provide the product as a pale yellow solid. Yield:30 mg, 0.09 mmol, 43%. LCMS m/z 333.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.96 (s, 1H), 8.55 (s, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.19 (m, 1H), 7.10(m, 1H), 6.79 (d, J=2.5 Hz, 1H), 2.24 (s, 6H), 2.03 (s, 3H), 1.51 (s,3H).

Example 24-[3-Methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]-1H-imidazo[4,5-c]pyridine

Step 1. Synthesis of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine(C6) and4-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-c]pyridine(C7)

To a solution of 4-chloro-1H-imidazo[4,5-c]pyridine (4.64 g, 30.2 mmol)in tetrahydrofuran (200 mL) was added sodium hydride (1.57 g, 39.3 mmol)at 0° C. The reaction mixture was stirred for 45 minutes at 0° C.,whereupon 2-(trimethylsilyl)ethoxymethyl chloride (6.55 g, 39.3 mmol)was added. Stirring was continued for 2 hours at 0° C., at which timethe reaction mixture was quenched with saturated aqueous ammoniumchloride solution and then extracted with dichloromethane (3×50 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to give a residue, which was purified by silica gelchromatography to afford a mixture of C6 and C7. Yield: 7.0 g, 24 mmol,80%. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (t, J=5.1 Hz, 2H), 8.18 (s, 1H),8.12 (s, 1H), 7.71 (d, J=5.6 Hz, 1H), 7.48 (d, J=5.6 Hz, 1H), 5.89 (s,2H), 5.59 (s, 2H), 3.65 (t, J=8.0 Hz, 2H), 3.55 (t, J=8.0 Hz, 2H), 0.97(m, 4H), 0.01 (s, 9H), 0.00 (s, 9H).

Step 2. Synthesis of (4-bromo-3-methylphenoxy)[tri(propan-2-yl)]silane(C8)

To a solution of 4-bromo-3-methylphenol (70 g, 0.374 mol) and1H-imidazole (51.52 g, 0.748 mol) in N,N-dimethylformamide (420 mL) wasadded tri(propan-2-yl)silyl chloride (88 mL, 0.41 mol) drop-wise. Thereaction mixture was stirred at room temperature overnight, then pouredinto water (1.5 L) and extracted with heptane (1.2 L). The organic layerwas washed with water (1 L) and with saturated aqueous sodium chloridesolution (400 mL), and dried over magnesium sulfate. The solvent wasremoved in vacuo to provide the product as a yellow oil. Yield: 137 g,0.37 mmol, 100% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J=8.7 Hz, 1H),6.76 (d, J=2.7 Hz, 1H), 6.64 (dd, J=8.5, 2.7 Hz, 1H), 2.32 (s, 3H), 1.22(m, 3H), 1.09 (d, J=8.0 Hz, 18H).

Step 3. Synthesis of[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy][tri(propan-2-yl)]silane(C9)

To a degassed solution of C8 (137 g, 0.374 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (190 g, 0.748mol) and potassium acetate (147 g, 1.49 mol) in 1,4-dioxane (1.3 L) wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.2g, 15 mmol), and the reaction mixture was heated at reflux overnight.The reaction mixture was filtered through diatomaceous earth, washingwith ethyl acetate, and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 3% ethyl acetate in heptane) afforded the product as ayellow oil. Yield: 131 g, 0.34 mmol, 90%. ¹H NMR (400 MHz, CDCl₃) δ 7.62(d, J=7.8 Hz, 1H), 6.65 (m, 2H), 2.47 (s, 3H), 1.31 (s, 12H), 1.27 (m,1H), 1.08 (d, J=8.0 Hz, 18H).

Step 4. Synthesis of3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenol (C10)

Water (17 μL, 0.94 mmol) was added to a suspension of5-bromo-6-methylimidazo[1,2-a]pyrazine (see A. R. Harris et al.,Tetrahedron 2011, 67, 9063-9066) (100 mg, 0.472 mmol), C9 (368 mg, 0.943mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35mg, 47 μmol) and potassium carbonate (130 mg, 0.943 mmol) in degassed1,2-dimethoxyethane (2 mL). The reaction mixture was heated at refluxfor 24 hours, then filtered through neutral diatomaceous earth, washingwith acetone (20 mL). The solvent was removed in vacuo and the residuewas purified by silica gel chromatography (Gradient: 0% to 10% methanolin ethyl acetate) to afford the product as a pale pink solid. Yield: 114mg, 0.47 mmol, quantitative yield. ¹H NMR (400 MHz, CD₃OD) δ 8.94 (s,1H), 7.72 (d, J=1.4 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.89(d, J=2.7 Hz, 1H), 6.83 (dd, J=8.2, 2.3 Hz, 1H), 2.29 (s, 3H), 1.94 (s,3H).

Step 5. Synthesis of4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-c]pyridine(C11) and4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-c]pyridine(C12)

To a solution of a mixture of C6 and C7 (100 mg, 0.35 mmol) in1,4-dioxane (5 mL) were added C10 (84 mg, 0.35 mmol),1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (BINAP, 43.5 mg, 0.07mmol), cesium carbonate (341 mg, 1.05 mmol), and palladium(II) acetate(7.84 mg, 35 μmol) at room temperature. The reaction mixture wasdegassed with nitrogen for 5 minutes and then heated to 120° C. for 4hours. After cooling to room temperature, it was filtered through a padof diatomaceous earth. The filtrate was concentrated in vacuo to providethe crude product (350 mg), which was used in the next step withoutfurther purification.

Step 6. Synthesis of4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]-1H-imidazo[4,5-c]pyridine(2)

To a mixture of C11 and C12 (from the previous step, 350 mg) was addedtrifluoroacetic acid (8 mL) at room temperature. The reaction mixturewas stirred for 1 hour at 80° C. and was then concentrated in vacuo andpurified by preparative HPLC to give the product. Yield: 46 mg, 0.13mmol, 37% over two steps. LCMS m/z 357.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)9.03 (s, 1H), 8.39 (s, 1H), 7.93 (d, J=5.8 Hz, 1H), 7.81 (d, J=1.0 Hz,1H), 7.54 (s, 1H), 7.45 (m, 2H), 7.39 (s, 1H), 7.31 (dd, J=8.0, 1.8 Hz,1H), 2.40 (s, 3H), 2.09 (s, 3H).

Examples 3, 4, and 56-[4-(Furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one(3),(−)-6-[4-(Furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one(4), and(+)-6-[4-(Furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one(5)

Step 1. Synthesis of 1-(4-methoxy-2-methylphenyl)propan-2-one (C13)

This experiment was carried out four times. Tributyl(methoxy)stannane(400 g, 1.24 mol), 1-bromo-4-methoxy-2-methylbenzene (250 g, 1.24 mol),prop-1-en-2-yl acetate (187 g, 1.87 mol), palladium(II) acetate (7.5 g,33 mmol) and tri-o-tolylphosphine (10 g, 33 mmol) were stirred togetherin toluene (2 L) at 100° C. for 18 hours. After it had cooled to roomtemperature, the reaction mixture was treated with aqueous potassiumfluoride solution (4 M, 400 mL) and stirred for 2 hours at 40° C. Theresulting mixture was diluted with toluene (500 mL) and filtered throughdiatomaceous earth; the filter pad was thoroughly washed with ethylacetate (2×1.5 L). The organic phase from the combined filtrates wasdried over sodium sulfate, filtered, and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 0% to 5% ethylacetate in petroleum ether) provided the product as a yellow oil.Combined yield: 602 g, 3.38 mol, 68%. LCMS m/z 179.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.05 (d, J=8.3 Hz, 1H), 6.70-6.77 (m, 2H), 3.79 (s, 3H),3.65 (s, 2H), 2.22 (s, 3H), 2.14 (s, 3H).

Step 2. Synthesis of 1-(4-methoxy-2-methylphenyl)propane-1,2-dione (C14)

Compound C13 (6.00 g, 33.7 mmol) and selenium dioxide (7.47 g, 67.3mmol) were suspended in 1,4-dioxane (50 mL) and heated at 100° C. for 18hours. The reaction mixture was cooled to room temperature and filteredthrough diatomaceous earth; the filtrate was concentrated in vacuo.Silica gel chromatography (Eluent: 10% ethyl acetate in heptane)afforded the product as a bright yellow oil. Yield: 2.55 g, 13.3 mmol,39%. LCMS m/z 193.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J=8.6 Hz,1H), 6.81 (br d, half of AB quartet, J=2.5 Hz, 1H), 6.78 (br dd, half ofABX pattern, J=8.7, 2.6 Hz, 1H), 3.87 (s, 3H), 2.60 (br s, 3H), 2.51 (s,3H).

Step 3. Synthesis of6-(4-methoxy-2-methylphenyl)-5-methylpyrazin-2(1H)-one (C15)

Compound C14 (4.0 g, 21 mmol) and glycinamide acetate (2.79 g, 20.8mmol) were dissolved in methanol (40 mL) and cooled to −10° C. Aqueoussodium hydroxide solution (12 N, 3.5 mL, 42 mmol) was added, and theresulting mixture was slowly warmed to room temperature. After stirringfor 3 days, the reaction mixture was concentrated in vacuo. The residuewas diluted with water, and 1 M aqueous hydrochloric acid was addeduntil the pH was approximately 7. The aqueous phase was extracted withethyl acetate, and the combined organic extracts were washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was slurried with 3:1 ethyl acetate/heptane, stirredfor 5 minutes, filtered, and concentrated in vacuo. Silica gelchromatography (Eluent: ethyl acetate) provided the product as a tansolid that contained 15% of an undesired regioisomer; this material wasused without further purification. Yield: 2.0 g. LCMS m/z 231.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.14 (d, J=8.2 Hz, 1H),6.82-6.87 (m, 2H), 3.86 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H).

Step 4. Synthesis of6-(4-methoxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (C16)

Compound C15 (from the previous step, 1.9 g) was dissolved inN,N-dimethylformamide (40 mL). Lithium bromide (0.86 g, 9.9 mmol) andsodium bis(trimethylsilyl)amide (95%, 1.91 g, 9.89 mmol) were added, andthe resulting solution was stirred for 30 minutes. Methyl iodide (0.635mL, 10.2 mmol) was added and stirring was continued at room temperaturefor 18 hours. The reaction mixture was then diluted with water andbrought to a pH of approximately 7 by slow portion-wise addition of 1 Maqueous hydrochloric acid. The aqueous layer was extracted with ethylacetate and the combined organic layers were washed several times withwater, dried over magnesium sulfate, filtered, and concentrated. Silicagel chromatography (Gradient: 75% to 100% ethyl acetate in heptane)afforded the product as a viscous orange oil. Yield: 1.67 g, 6.84 mmol,33% over two steps. LCMS m/z 245.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.17 (s, 1H), 7.03 (br d, J=8 Hz, 1H), 6.85-6.90 (m, 2H), 3.86 (s, 3H),3.18 (s, 3H), 2.08 (br s, 3H), 2.00 (s, 3H).

Step 5. Synthesis of6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (C17)

To a −78° C. solution of C16 (1.8 g, 7.4 mmol) in dichloromethane (40mL) was added a solution of boron tribromide in dichloromethane (1 M, 22mL, 22 mmol). The cooling bath was removed after 30 minutes, and thereaction mixture was allowed to warm to room temperature and stir for 18hours. The reaction was cooled to −78° C., and methanol (10 mL) wasslowly added; the resulting mixture was gradually warmed to roomtemperature. After the solvent had been removed in vacuo, methanol (20mL) was added, and the mixture was again concentrated under reducedpressure. The residue was diluted with ethyl acetate (300 mL) and water(200 mL), the aqueous layer was brought to pH 7 via portion-wiseaddition of saturated aqueous sodium carbonate solution, and the mixturewas extracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water and with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered, and concentrated invacuo to afford the product as a light tan solid. Yield: 1.4 g, 6.0mmol, 81%. LCMS m/z 231.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s,1H), 6.98 (d, J=8.2 Hz, 1H), 6.87-6.89 (m, 1H), 6.85 (br dd, J=8.2, 2.5Hz, 1H), 3.22 (s, 3H), 2.06 (br s, 3H), 2.03 (s, 3H).

Step 6. Synthesis of6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one(3),(−)-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one(4), and(+)-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one(5)

To a stirred solution of C3 (60 mg, 0.39 mmol) in dimethyl sulfoxide (2mL) was added C17 (121 mg, 0.39 mmol) and cesium carbonate (379 mg, 1.16mmol). The reaction mixture was stirred at 120° C. for 3 hours, cooledto room temperature, and partitioned between ethyl acetate and water.The aqueous layer was extracted three times with ethyl acetate, and thecombined organic layers were washed sequentially with water and withsaturated aqueous sodium chloride solution, then dried over sodiumsulfate. The solvent was removed in vacuo and the residue was purifiedvia silica gel chromatography (Gradient: 0% to 30% [80:20:1dichloromethane/methanol/concentrated ammonium hydroxide] indichloromethane) to provide product 3, a mixture of atropenantiomers, asa light yellow foam. Yield: 108 mg, 0.31 mmol, 80%. LCMS m/z 349.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.22 (s, 1H), 7.72 (d,J=2.5 Hz, 1H), 7.18-7.35 (m, 3H), 6.91 (d, J=2.4 Hz, 1H), 3.26 (s, 3H),2.18 (s, 3H), 2.08 (s, 3H).

Compound Example 3 was separated into its atropenantiomers viasupercritical fluid chromatography Column: Chiral Technologies ChiralcelOJ-H, 5 μm; Eluent: 3:1 carbon dioxide/2-propanol). Example 4[designated the (−)-atropenantiomer according to its observed rotationdata] was the first-eluting isomer, followed by Example 5. Example 5 wasdesignated the (+)-atropenantiomer according to its observed rotationdata.

4: LCMS m/z 349.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.11(s, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.36-7.41 (m, 2H), 7.33 (br dd, half ofABX pattern, J=8, 2 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 3.27 (s, 3H), 2.18(s, 3H), 2.06 (s, 3H).

5: LCMS m/z 349.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.11(s, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.36-7.41 (m, 2H), 7.33 (br dd, half ofABX pattern, J=8, 2 Hz, 1H), 7.00 (d, J=2.5 Hz, 1H), 3.27 (s, 3H), 2.18(s, 3H), 2.06 (s, 3H).

Examples 6, 7, and 8 5-[4-(Furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one(6),(+)-5-[4-(Furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one(7), and(−)-5-[4-(Furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one(8)

Step 1. Synthesis of 4-hydroxy-3,5-dimethylfuran-2(5H)-one (C18)

Methylation of ethyl 3-oxopentanoate according to the method of D.Kalaitzakis et al., Tetrahedron: Asymmetry 2007, 18, 2418-2426, affordedethyl 2-methyl-3-oxopentanoate; subsequent treatment with 1 equivalentof bromine in chloroform provided ethyl4-bromo-2-methyl-3-oxopentanoate. This crude material (139 g, 586 mmol)was slowly added to a 0° C. solution of potassium hydroxide (98.7 g,1.76 mol) in water (700 mL). The internal reaction temperature rose to30° C. during the addition. The reaction mixture was then subjected tovigorous stirring for 4 hours in an ice bath, at which point it wasacidified via slow addition of concentrated hydrochloric acid. Afterextraction with ethyl acetate, the aqueous layer was saturated withsolid sodium chloride and extracted three additional times with ethylacetate. The combined organic layers were washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to afford a mixture of oil and solid(81.3 g). This material was suspended in chloroform (200 mL); the solidswere removed via filtration and washed with chloroform (2×50 mL). Thecombined filtrates were concentrated in vacuo and treated with a 3:1mixture of heptane and diethyl ether (300 mL). The mixture wasvigorously swirled until some of the oil began to solidify, whereupon itwas concentrated under reduced pressure to afford an oily solid (60.2g). After addition of a 3:1 mixture of heptane and diethyl ether (300mL) and vigorous stirring for 10 minutes, filtration afforded theproduct as an off-white solid. Yield: 28.0 g, 219 mmol, 37%. ¹H NMR (400MHz, CDCl₃) δ 4.84 (br q, J=6.8 Hz, 1H), 1.74 (br s, 3H), 1.50 (d, J=6.8Hz, 3H).

Step 2. Synthesis of 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (C19)

Trifluoromethanesulfonic anhydride (23.7 mL, 140 mmol) was addedportion-wise to a solution of C18 (15.0 g, 117 mmol) andN,N-diisopropylethylamine (99%, 24.8 mL, 140 mmol) in dichloromethane(500 mL) at −20° C., at a rate sufficient to maintain the internalreaction temperature below −10° C. The reaction mixture was allowed towarm gradually from −20° C. to 0° C. over 5 hours. It was then passedthrough a plug of silica gel, dried over magnesium sulfate, andconcentrated in vacuo. The residue was suspended in diethyl ether andfiltered; the filtrate was concentrated under reduced pressure.Purification using silica gel chromatography (Gradient: 0% to 17% ethylacetate in heptane) afforded the product as a pale yellow oil. Yield:21.06 g, 80.94 mmol, 69%. ¹H NMR (400 MHz, CDCl₃) δ 5.09-5.16 (m, 1H),1.94-1.96 (m, 3H), 1.56 (d, J=6.6 Hz, 3H).

Step 3. Synthesis of2-[4-(benzyloxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(C20)

A mixture of benzyl 4-bromo-3-methylphenyl ether (19.0 g, 68.6 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.5 g, 10mmol), potassium acetate (26.9 g, 274 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (20 g, 79mmol) in 1,4-dioxane (500 mL) was heated at reflux for 2 hours. Thereaction mixture was then filtered through diatomaceous earth, and thefiltrate was concentrated in vacuo. Silica gel chromatography (Gradient:0% to 1% ethyl acetate in petroleum ether) provided the product as ayellow gel. Yield: 15 g, 46 mmol, 67%. ¹H NMR (400 MHz, CDCl₃) δ 7.73(d, J=8.0 Hz, 1H), 7.30-7.46 (m, 5H), 6.76-6.82 (m, 2H), 5.08 (s, 2H),2.53 (s, 3H), 1.34 (s, 12H).

Step 4. Synthesis of4-[4-(benzyloxy)-2-methylphenyl]-3,5-dimethylfuran-2(5H)-one (C21)

Compound C19 (5.0 g, 19 mmol), C20 (7.48 g, 23.1 mmol),tetrakis(triphenylphosphine)palladium(0) (2.22 g, 1.92 mmol), and sodiumcarbonate (4.07 g, 38.4 mmol) were combined in 1,4-dioxane (100 mL) andwater (5 mL), and heated at reflux for 2 hours. The reaction mixture wasfiltered and the filtrate was concentrated in vacuo. Silica gelchromatography (Eluents: 10:1, then 5:1 petroleum ether/ethyl acetate)provided the product as a white solid. Yield: 5.8 g, 19 mmol, 100%. NMR(400 MHz, CDCl₃) δ 7.33-7.49 (m, 5H), 6.98 (d, J=8.5 Hz, 1H), 6.94 (brd, J=2.5 Hz, 1H), 6.88 (br dd, J=8.3, 2.5 Hz, 1H), 5.20 (qq, J=6.7, 1.8Hz, 1H), 5.09 (s, 2H), 2.21 (s, 3H), 1.78 (d, J=1.8 Hz, 3H), 1.31 (d,J=6.8 Hz, 3H).

Step 5. Synthesis of4-[4-(benzyloxy)-2-methylphenyl]-5-hydroxy-3,5-dimethylfuran-2(5H)-one(C22)

A solution of C21 (5.4 g, 18 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (13.3 g, 87.4 mmol) in acetonitrile(100 mL) was cooled to −60° C. Oxygen was bubbled into the reactionmixture for 20 minutes at −60° C.; the solution was then stirred at 50°C. for 18 hours. The reaction mixture was concentrated in vacuo andpurified via silica gel chromatography (Eluent: 5:1 petroleumether/ethyl acetate) to provide the product as a colorless oil. Yield:3.5 g, 11 mmol, 61%. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ7.33-7.49 (m, 5H), 6.92-6.96 (m, 1H), 6.88 (dd, J=8.5, 2.5 Hz, 1H), 5.09(s, 2H), 2.20 (s, 3H), 1.73 (s, 3H).

Step 6. Synthesis of5-[4-(benzyloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one (C23)

A mixture of C22 (3.5 g, 11 mmol) and hydrazine hydrate (85% in water,1.9 g, 32 mmol) in n-butanol (60 mL) was heated at reflux for 18 hours.After removal of volatiles under reduced pressure, the residue wasstirred with ethyl acetate (20 mL) for 30 minutes, whereupon filtrationprovided the product as a white solid. Yield: 2.0 g, 6.2 mmol, 56%. ¹HNMR (400 MHz, CDCl₃) δ 10.93 (br s, 1H), 7.33-7.51 (m, 5H), 6.96 (s,1H), 6.88-6.94 (m, 2H), 5.10 (s, 2H), 2.04 (s, 3H), 1.95 (s, 3H), 1.91(s, 3H).

Step 7. Synthesis of5-[4-(benzyloxy)-2-methylphenyl]-4,6-dimethyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(C24)

A mixture of C23 (17.8 g, 55.6 mmol), 3,4-dihydro-2H-pyran (233 g, 2.77mol) and p-toluenesulfonic acid monohydrate (2.1 g, 11 mmol) intetrahydrofuran (800 mL) was heated at reflux for 18 hours.Triethylamine (10 mL, 72 mmol) was added, and the mixture wasconcentrated in vacuo. Silica gel chromatography (Gradient: 0% to 25%ethyl acetate in petroleum ether) afforded the product as a solid,presumed to be a mixture of diastereomeric atropisomers from its ¹H NMRspectrum. Yield: 20 g, 49 mmol, 88%. ¹H NMR (400 MHz, CDCl₃),characteristic peaks: δ 7.32-7.50 (m, 5H), 6.82-6.96 (m, 3H), 6.15 (brd, J=10.3 Hz, 1H), 5.08 (s, 2H), 4.14-4.23 (m, 1H), 3.76-3.85 (m, 1H),2.28-2.41 (m, 1H), 2.01 and 2.04 (2 s, total 3H), 1.97 and 1.98 (2 s,total 3H), 1.89 and 1.89 (2 s, total 3H).

Step 8. Synthesis of5-(4-hydroxy-2-methylphenyl)-4,6-dimethyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(C25)

Palladium (10% on carbon, 1.16 g, 1.09 mmol) was added to a solution ofC24 (1.47 g, 3.63 mmol) in methanol (30 mL) and ethyl acetate (10 mL),and the mixture was hydrogenated (50 psi) on a Parr shaker for 18 hoursat room temperature. The reaction mixture was filtered throughdiatomaceous earth, and the filter pad was rinsed with ethyl acetate;the combined filtrates were concentrated in vacuo and triturated withheptane, affording the product as a white solid, judged to be a mixtureof diastereomeric atropisomers from its ¹H NMR spectrum. Yield: 1.01 g,3.21 mmol, 88%. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ6.74-6.85 (m, 3H), 6.12-6.17 (m, 1H), 4.15-4.23 (m, 1H), 3.76-3.84 (m,1H), 2.28-2.41 (m, 1H), 1.99 and 2.01 (2 s, total 3H), 1.97 and 1.98 (2s, total 3H), 1.89 and 1.89 (2 s, total 3H).

Step 9. Synthesis of5-(4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl)-4,6-dimethyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(C26)

To a resealable pressure tube were added C3 (38.9 mg, 0.25 mmol), C25(66 mg, 0.21 mmol), cesium carbonate (205 mg, 0.63 mmol) and dimethylsulfoxide (15 mL). The reaction mixture was heated to 120° C. for 6hours, then cooled to room temperature and diluted with ethyl acetate.The mixture was washed sequentially with water and with saturatedaqueous sodium chloride solution, then dried over magnesium sulfate. Thesolvent was removed in vacuo and the residue was used in the next stepwithout further purification. LCMS m/z 433.1 [M+H]⁺.

Step 10. Synthesis of5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one(6)

To a solution of C26 (from the previous step, ≤0.21 mmol) indichloromethane was added a solution of hydrogen chloride in 1,4-dioxane(4 M, 1.61 mL, 6.45 mmol). The reaction mixture was stirred at roomtemperature overnight, whereupon it was partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The aqueouslayer was extracted three times with ethyl acetate, and the combinedorganic layers were dried over sodium sulfate. The solvent was removedin vacuo and the resulting solid was triturated with diethyl ether toafford the product as a tan solid. Yield: 56.5 mg, 0.16 mmol, 76% overtwo steps. LCMS m/z 349.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s,1H), 7.68 (d, J=2.5 Hz, 1H), 7.26-7.28 (m, 1H, assumed; partiallyobscured by solvent peak), 7.23 (br dd, J=8, 2 Hz, 1H), 7.08 (d, J=8 Hz,1H), 6.83 (d, J=2.5 Hz, 1H), 2.11 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H).

Step 11. Isolation of (+)-5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4, 6-dimethylpyridazin-3(2H)-one(7) and(+5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one(8)

Compound 6 was separated into its atropenantiomers using supercriticalfluid chromatography (Column: Chiral Tech OJ-H, 5 μm; Eluent: 4:1 carbondioxide/methanol). Example 7 (designated the (+)-atropenantiomeraccording to its observed rotation data) was the first-eluting isomer,followed by Example 8. Example 8 was designated the (−)-atropenantiomeraccording to its observed rotation data.

7: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.70 (d, J=2.4 Hz, 1H),7.21-7.27 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 2.13(s, 3H), 2.04 (s, 3H), 1.99 (s, 3H).

8: ¹H NMR (400 MHz, CDCl₃) δ 10.83 (br s, 1H), 8.58 (s, 1H), 7.70 (d,J=2.4 Hz, 1H), 7.21-7.26 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.84 (d, J=2.4Hz, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H).

Example 96-[4-(Furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione(9)

Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione,hydrochloride salt (C27)

A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) wasadded to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol)and 1-methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and thereaction mixture was heated at reflux for 18 hours, then cooled to roomtemperature. After removal of solvent in vacuo, the residue wasrepeatedly evaporated under reduced pressure with acetonitrile (3×50mL), then partitioned between acetonitrile (100 mL) and water (100 mL).Aqueous 6 M hydrochloric acid was slowly added until the pH had reachedapproximately 2; the resulting mixture was stirred for 1 hour. Theprecipitate was collected via filtration and washed with tert-butylmethyl ether, affording the product as a white solid. Yield: 15.2 g,79.3 mmol, 80%. LCMS m/z 156.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38(br s, 1H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H).

Step 2. Synthesis of 6-bromo-1,5-dimethylpyrimidine-2,4(1H,3H)-dione(C28)

A 1:1 mixture of acetonitrile and water (120 mL) was added to a mixtureof C27 (9.50 g, 49.6 mmol), sodium nitrite (5.24 g, 76 mmol), andcopper(II) bromide (22.4 g, 100 mmol) {Caution: bubbling and slightexotherm!}, and the reaction mixture was allowed to stir at roomtemperature for 66 hours. Addition of aqueous sulfuric acid (1 N, 200mL) and ethyl acetate (100 mL) provided a precipitate, which wascollected via filtration and washed with water and ethyl acetate toafford the product as a light yellow solid (7.70 g). The organic layerof the filtrate was concentrated to a smaller volume, during whichadditional precipitate formed; this was isolated via filtration andwashed with 1:1 ethyl acetate/heptane to provide additional product (0.4g). Total yield: 8.1 g, 37 mmol, 75%. GCMS m/z 218, 220 [M⁺]. ¹H NMR(400 MHz, DMSO-d₆) δ 11.58 (br s, 1H), 3.45 (s, 3H), 1.93 (s, 3H).

Step 3. Synthesis of6-bromo-3-(3,4-dimethoxybenzyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione(C29)

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 98%, 5.57 mL, 36.5 mmol) wasadded to a suspension of C28 (4.00 g, 18.3 mmol) and4-(chloromethyl)-1,2-dimethoxybenzene (5.16 g, 27.6 mmol) inacetonitrile (80 mL), and the reaction mixture was heated at 60° C. for18 hours. After removal of solvent in vacuo, the residue was purifiedvia silica gel chromatography (Gradient: 25% to 50% ethyl acetate inheptane) to afford the product as a white solid. Yield: 5.70 g, 15.4mmol, 84%. ¹H NMR (400 MHz, CDCl₃) δ 7.08-7.12 (m, 2H), 6.80 (d, J=8.0Hz, 1H), 5.07 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 2.14(s, 3H).

Step 4. Synthesis of3-(3,4-dimethoxybenzyl)-6-(4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H, 3H)-dione (C30)

To a solution of C29 (3.5 g, 9.5 mmol) in 1,4-dioxane (100 mL) wereadded 4-hydroxyphenyl boronic acid (2.7 g, 19 mmol),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,dichloromethane complex (592 mg, 0.711 mmol), and aqueous potassiumcarbonate solution (3 M, 9 mL, 27 mmol). The reaction mixture was heatedat 100° C. overnight, then cooled to room temperature, diluted withethyl acetate and water, and filtered through diatomaceous earth toremove solids. The organic layer was washed sequentially with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, then dried over magnesium sulfate. The solvent wasremoved in vacuo and the residue was purified by silica gelchromatography (Gradient: 25% to 50% ethyl acetate in heptane) to affordthe product as a white solid. Yield: 3.4 g, 8.9 mmol, 94%. LCMS m/z383.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.20 (m, 2H), 7.05 (m, 2H), 6.96(m, 2H), 6.82 (d, J=8.0 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H), 3.86 (s,3H), 3.06 (s, 3H), 1.70 (s, 3H).

Step 5. Synthesis of6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione(9)

The title compound was generated as part of a library using thefollowing protocol: to a 2-dram vial were added C3 (0.13 mmol), C30(38.2 mg, 0.1 mmol), cesium carbonate (98 mg, 0.3 mmol),di-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane(10 mg, 20 μmol) and degassed 1,4-dioxane (1 mL). The reaction wasdegassed with nitrogen and shaken and heated at 110° C. for 20 hours.The reaction mixture was then partitioned between water (1.5 mL) andethyl acetate (2.5 mL) and filtered through diatomaceous earth; theorganic layer was eluted through a solid-phase extraction cartridgecharged with sodium sulfate, and the filtrate was concentrated in vacuo.The residue was treated with methoxybenzene (0.1 mL) and trifluoroaceticacid (1.25 mL), and this reaction mixture was shaken and heated at 90°C. for 48 hours, whereupon it was concentrated. The residue (35 mg) waspurified via reversed phase HPLC (Column: Waters XBridge C18, 5 μm;Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B:0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 5% to 100% B).Yield: 2.6 mg, 7.4 μmol, 7%. LCMS m/z 351.2 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 8.58 (s, 1H), 8.18 (d, J=2.4 Hz, 1H), 7.51 (br AB quartet,J_(AB)=8.7 Hz, Δν_(AB)=11.1 Hz, 4H), 7.07 (d, J=2.4 Hz, 1H), 2.94 (s,3H), 1.56 (s, 3H).

Example 104,6-Dimethyl-5-[2-methyl-4-([1,2]thiazolo[4,5-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one(10)

Step 1. Synthesis of4-(tert-butylsulfanyl)-2-chloropyridine-3-carbaldehyde (C31)

A mixture of 2,4-dichloropyridine-3-carbaldehyde (838 mg, 4.76 mmol),2-methylpropane-2-thiol (429 mg, 4.76 mmol), and potassium carbonate(987 mg, 4.76 mmol) in N,N-dimethylformamide (10 mL) was heated at 50°C. for 3 hours. After the reaction mixture had been cooled to roomtemperature, it was diluted with water and extracted withdichloromethane (3×30 mL). The combined organic layers were washed withwater (3×15 mL) and dried over magnesium sulfate. The solvent wasremoved in vacuo and the residue was purified by silica gelchromatography (Gradient: 0% to 20% ethyl acetate in heptane) to affordthe product as a yellow oil. Yield: 840 mg, 3.66 mmol, 77%. LCMS m/z230.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.56 (s, 1H), 8.30 (d, J=5.5Hz, 1H), 7.52 (d, J=5.5 Hz, 1H), 1.55 (s, 9H).

Step 2. Synthesis of(E)-1-[4-(tert-butylsulfanyl)-2-chloropyridin-3-yl]-N-hydroxymethanimine(C32)

To a stirred solution of C31 (840 mg, 3.66 mmol) inN,N-dimethylformamide (10 mL) at room temperature were addedhydroxylamine hydrochloride (145 mg, 4.39 mmol) and sodium bicarbonate(1.84 g, 21.9 mmol). The reaction mixture was stirred at roomtemperature overnight, and then heated to 50° C. for 2 hours. Thereaction mixture was cooled to room temperature and diluted with ethylacetate, washed with water and with saturated aqueous sodium chloridesolution, and dried over magnesium sulfate. The solvent was removed invacuo and the residue was purified by silica gel chromatography(Gradient: 0% to 20% ethyl acetate in heptane) to afford the product asa white solid. Yield: 482 mg, 1.97 mmol, 54%. LCMS m/z 245.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.28 (d, J=5.5 Hz, 1H), 7.68 (d,J=5.5 Hz, 1H), 1.50 (s, 9H).

Step 3. Synthesis of1-[({(E)-[4-(tert-butylsulfanyl)-2-chloropyridin-3-yl]methylidene}amino)oxy]ethanone(C33)

A mixture of C32 (250 mg, 1.02 mmol) and acetic anhydride (225 mg, 2.05mmol) in pyridine (10 mL) was heated at reflux for 1 hour. The reactionmixture was cooled to room temperature, diluted with ethyl acetate, andwashed with saturated aqueous potassium carbonate solution. The organiclayer was dried over magnesium sulfate, filtered, and concentrated invacuo; the residue was purified via chromatography on silica gel(Gradient: 0% to 20% ethyl acetate in heptane) to afford the product asa white solid. Yield: 199 mg, 0.69 mmol, 68%. LCMS m/z 284.9 [M−H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 7.48 (d,J=5.5 Hz, 1H), 2.30 (s, 3H), 1.49 (s, 3H).

Step 4. Synthesis of 4-chloro[1,2]thiazolo[4,5-c]pyridine (C34)

A solution of C33 (170 mg, 0.59 mmol) in dimethyl sulfoxide (5 mL) washeated at 100° C. for 5 hours, whereupon it was cooled to roomtemperature and diluted with dichloromethane. The mixture was washedsequentially with water and with saturated aqueous sodium chloridesolution, then dried over magnesium sulfate. The solvent was removed invacuo and the residue was purified by silica gel chromatography(Gradient: 0% to 20% ethyl acetate in heptane) to afford the product asa white solid. Yield: 55 mg, 0.32 mmol, 54%. LCMS m/z 171.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 7.83 (dd,J=5.7, 1 Hz, 1H).

Step 5. Synthesis of4,6-dimethyl-5-[2-methyl-4-([1,2]thiazolo[4,5-c]pyridin-4-yloxy)phenyl]-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(C35)

To a solution of C25 (122 mg, 0.39 mmol) in 1,4-dioxane (5 mL) wereadded C34 (55 mg, 0.32 mmol), cesium carbonate (316 mg, 0.97 mmol),palladium(II) acetate (7.4 mg, 33 μmol) anddi-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane(31 mg, 62 μmol). The reaction mixture was heated to 80° C. overnight,then cooled to room temperature and filtered through diatomaceous earth.The filter pad was rinsed with ethyl acetate. The combined filtrateswere concentrated in vacuo and the residue was purified first bychromatography on silica gel (Gradient: 0% to 100% ethyl acetate inheptane, followed by elution with 20% methanol in dichloromethane) andthen via reversed phase HPLC (Column: Phenomenex Gemini NX-C18, 5 μm;Mobile phase A: 0.1% ammonium hydroxide in water; Mobile phase B: 0.1%ammonium hydroxide in methanol; Gradient: 50% to 100% B) to afford theproduct as a white solid. Yield: 16 mg, 36 μmol, 11%. LCMS m/z 447.2[M−H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=5.5 Hz, 1H), 8.03 (d, J=5.5Hz, 1H), 7.33 (d, J=5.5 Hz, 1H), 7.12 (m, 1H), 7.00 (m, 2H), 6.13 (m,1H), 4.19 (m, 2H), 3.79 (m, 1H), 2.32 (m, 1H), 2.05 (s, 3H), 1.99 (s,3H), 1.91 (s, 3H), 1.74 (m, 2H), 1.54 (m, 2H).

Step 6. Synthesis of4,6-dimethyl-5-[2-methyl-4-([1,2]thiazolo[4,5-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one(10)

To a stirred solution of C35 (41 mg, 91 μmol) in dichloromethane (5 mL)was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.68 mL,2.7 mmol). The reaction mixture was stirred at room temperature for 3hours, whereupon it was partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate solution. The aqueous layer was extractedthree times with ethyl acetate, and the combined organic layers weredried over sodium sulfate. The solvent was removed in vacuo and theresidue was triturated with diethyl ether to afford the product as awhite solid. Yield: 29 mg, 79 μmol, 87%. LCMS m/z 365.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.10 (d, J=5.7 Hz, 1H), 7.60 (dd,J=5.8, 0.9 Hz, 1H), 7.26 (m, 2H), 7.24 (m, 1H), 7.09 (d, J=8.2 Hz, 1H),2.12 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H).

PREPARATIONS

Preparations bleow describe preparation of P1 that can be used asstarting materials for preparation of certain examples of compounds ofthe invention.

Preparation P15-(4-Hydroxy-2-methylphenyl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(P1)

Step 1. Synthesis of4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (C36)

A mixture of 4,5-dichloropyridazin-3-ol (42 g, 250 mmol),3,4-dihydro-2H-pyran (168 g, 2.00 mol) and p-toluenesulfonic acid (8.8g, 51 mmol) in tetrahydrofuran (2 L) was heated at reflux for 2 days.After cooling to room temperature, the reaction mixture was concentratedin vacuo and purified by silica gel chromatography (Gradient: 3% to 5%ethyl acetate in petroleum ether). The product was obtained as a whitesolid. Yield: 42 g, 170 mmol, 68%. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (s,1H), 6.01 (br d, J=11 Hz, 1H), 4.10-4.16 (m, 1H), 3.70-3.79 (m, 1H),1.99-2.19 (m, 2H), 1.50-1.80 (m, 4H).

Step 2. Synthesis of4-chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (C37)and 5-chloro-4-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(C38)

To a mixture of C36 (40 g, 0.16 mol), methylboronic acid (9.6 g, 0.16mol) and cesium carbonate (156 g, 479 mmol) in 1,4-dioxane (500 mL) andwater (50 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 g, 7mmol). The reaction mixture was stirred at 110° C. for 2 hours,whereupon it was cooled to room temperature and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 3% to 6% ethylacetate in petroleum ether) afforded compound C37 as a pale yellowsolid. Yield: 9.0 g, 39 mmol, 24%. LCMS m/z 250.8 [M+Na⁺]. ¹H NMR (400MHz, CDCl₃) δ 7.71 (s, 1H), 6.07 (dd, J=10.7, 2.1 Hz, 1H), 4.10-4.18 (m,1H), 3.71-3.81 (m, 1H), 2.30 (s, 3H), 1.98-2.19 (m, 2H), 1.53-1.81 (m,4H). Also obtained was C38, as a pale yellow solid. Yield: 9.3 g, 41mmol, 26%. LCMS m/z 250.7 [M+Na⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s,1H), 6.02 (dd, J=10.7, 2.1 Hz, 1H), 4.10-4.17 (m, 1H), 3.71-3.79 (m,1H), 2.27 (s, 3H), 1.99-2.22 (m, 2H), 1.51-1.79 (m, 4H).

Step 3. Synthesis of5-[4-(benzyloxy)-2-methylphenyl]-4-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(C39)

A solution of C20 (7.30 g, 22.5 mmol), C38 (2.7 g, 12 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.3 g, 1.8mmol) and cesium carbonate (7.7 g, 24 mmol) in 1,4-dioxane (100 mL) washeated at reflux for 7 hours. The reaction mixture was then filteredthrough a pad of diatomaceous earth, and the filtrate was concentratedin vacuo. Silica gel chromatography (Gradient: 10% to 50% ethyl acetatein petroleum ether) afforded the product as a brown gel, presumed to bea mixture of diastereomeric atropisomers from its ¹H NMR spectrum.Yield: 2.5 g, 6.4 mmol, 53%. ¹H NMR (400 MHz, CDCl₃), characteristicpeaks: δ 7.66 (s, 1H), 7.35-7.49 (m, 5H), 6.96-7.03 (m, 1H), 6.94 (br d,J=2 Hz, 1H), 6.89 (dd, J=8.3, 2 Hz, 1H), 6.14-6.20 (m, 1H), 5.10 (s,2H), 4.15-4.24 (m, 1H), 3.76-3.86 (m, 1H), 2.18-2.32 (m, 1H), 2.12 and2.14 (2 s, total 3H), 2.00 (s, 3H), 1.71-1.86 (m, 3H).

Step 4. Synthesis of5-(4-hydroxy-2-methylphenyl)-4-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(P1)

A mixture of C39 (2.5 g, 6.4 mmol) and wet palladium on carbon (0.8 g)in methanol (80 mL) was stirred under 50 psi of hydrogen for 3 days,whereupon the reaction mixture was filtered through diatomaceous earth.The filtrate was concentrated in vacuo, and the residue was purified viasilica gel chromatography (Gradient: 10% to 60% ethyl acetate inpetroleum ether) to provide the product as a white solid, judged to be amixture of diastereomeric atropisomers from its ¹H NMR spectrum. Yield:1.6 g, 5.3 mmol, 83%. LCMS m/z 301 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃),characteristic peaks: δ 7.64-7.68 (s, 1H), 6.90-6.97 (m, 1H), 6.73-6.82(m, 2H), 6.14-6.19 (m, 1H), 4.14-4.23 (m, 1H), 3.76-3.85 (m, 1H),2.17-2.31 (m, 1H), 2.09 and 2.11 (2 s, total 3H), 2.00 (s, 3H),1.72-1.85 (m, 3H).

Table 1 below lists some additional examples of compounds of invention(Examples 11-23) that were made using methods, starting materials orintermediates, and preparations described herein.

TABLE 1 Examples 11-23 (including Method of Preparation, Non-Commercialstarting materials, Structures and Physicochemical Data). Method of ¹HNMR (600 MHz, DMSO-d₆) δ (ppm); Preparation; Mass spectrum, observed ionm/z Non-commercial [M + H]⁺ or HPLC retention time; Mass Examplestarting spectrum m/z [M + H]⁺ (unless otherwise number materialsStructure indicated) 11 Example 2; C5

¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 8.36 (s, 1H), 7.89 (d, J = 5.8Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 7.27 (s, 1H), 7.19 (s, 2H), 2.71 (s,6H), 2.05 (s, 3H); 332.1 12 Example 2¹

¹H NMR (400 MHz, CD₃OD) δ 9.21 (s, 1H), 8.38 (s, 1H), 7.94 (d, J = 5.8Hz, 1H), 7.45 (d, J = 4.0 Hz, 1H), 7.33 (m, 2H), 7.25 (d, J = 9.8 Hz,1H), 2.47 (s, 3H), 2.15 (s, 3H); 343.0 13 Example 6²

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.36(m, 2H), 7.26 (m, 2H), 7.33 (m, 2H), 6.86 (d, J = 2.5 Hz, 1H), 1.99 (s,3H), 1.88 (s, 3H); 335.2 14 Example 6³; P1

Retention time, 2.44 minutes; 335.0 15 Example 9⁴; C30

8.19 (d, J = 6.1 Hz, 1H), 7.53 (d, J = 6.1 Hz, 1H), 7.49 (d, J = 8.6,2H), 7.47 (d, J = 8.6 Hz, 1H), 2.94 (s, 3H), 2.71 (s, 3H), 1.58 (s, 3H);365.0 16 Example 6; C25

8.19 (d, J = 6.1 Hz, 1H), 7.51 (d, J = 6.1 Hz, 1H), 7.32 (s, 1H), 7.26(dd, J = 8.6, 2.2 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 2.69 (s, 3H), 2.49(s, 3H), 2.04 (s, 3H), 1.88 (s, 3H); 363.1 17 Example 3; C17

8.20 (d, J = 6.1 Hz, 1H), 8.03 (s, 1H), 7.52 (d, J = 6.1 Hz, 1H), 7.39(dd, J = 8.3, 2.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 3.08 (s, 3H), 2.69(s, 3H), 2.10 (s, 3H), 1.93 (s, 3H); 363.1 18 Example 9⁵

8.59 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.52 (s, br, 4H), 7.05 (d, J =2.2 Hz, 1H), 2.92 (s, 3H), 1.97 (q, J = 7.3 Hz, 2H), 0.86 (t, J = 7.3Hz, 3H); 365.2 19 Example 9⁶

8.57 (s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.49 (m, br, 4H), 7.03 (d, J =2.6 Hz, 1H), 3.61 (t, J = 6.1 Hz, 2H), 3.34 (t, J = 6.1 Hz, 2H) 3.09 (s,3H), 1.51 (s, 3H); 395.2 20 Example 9⁷

8.59 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.53 (s, br, 4H), 7.05 (d, J =2.2 Hz, 1H), 3.49 (q, J = 7.0 Hz, 2H), 1.52 (s, 3H), 0.98 (t, J = 7.0Hz, 3H); 365.2 21 Example 9⁸

8.57 (s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.54 (dt, J = 9.6, 0.7 Hz, 2H),7.45 (dt, J = 9.6, 0.7 Hz, 2H), 7.03 (d, J = 2.6 Hz, 1H), 2.6 (m, 1H),1.60 (s, 3H), 0.57 (m, 2H), 0.51 (m, 2H); 377.2 22 Example 9⁹

8.58 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.46(d, J = 8.8 Hz, 2H), 7.01 (d, J = 2.2 Hz, 1H), 2.54 (q, J = 7.3 Hz, 2H),2.03 (t, J = 7.3 Hz, 3H); 391.2 23 Example 9¹⁰

8.60 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.53(d, J = 8.8 Hz, 2H), 7.02 (d, J = 2.2 Hz, 1H), 3.45 (q, J = 7.0 Hz, 2H),1.93 (q, J = 7.5 Hz, 2H), 0.99 (t, J = 7.0 Hz, 3H), 0.85 (t, J = 7.5 Hz,3H); 379.2 ¹The requisite intermediate5-(4-hydroxy-2-methylphenyl)-6-methylpyrimidine-4-carbonitrile wasprepared following a procedure similar to that described for thepreparation of C5 from 5-bromo-6-methylpyrimidine-4-carbonitrile. Thefinal product was obtained following the coupling and deprotectionconditions described in the preparation of Example 2. ²The requisite5-(4-hydroxyphenyl)-4,6-dimethyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-onewas prepared from 1-(benzyloxy)-4-bromobenzene following the proceduredescribed for preparation of C25. ³Analytical HPLC conditions. Column:Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: 0.05%trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95.0% B,linear, over 4.0 minutes; Flow rate: 2 mL/minute. ⁴The final couplingstep was carried out using cesium carbonate in dimethyl sulfoxide at 80°C. ⁵The requisite3-(3,4-dimethoxybenzyl)-5-ethyl-6-(4-hydroxyphenyl)-1-methylpyrimidine-2,4(1H,3H)-dionewas prepared following a procedure similar to that described for thepreparation of C30, starting from ethyl 2-cyanobutanoate and1-methylurea. ⁶The requisite3-(3,4-dimethoxybenzyl)-6-(4-hydroxyphenyl)-1-(2-methoxyethyl)-5-methylpyrimidine-2,4(1H,3H)-dionewas prepared following a procedure similar to that described for thepreparation of C30, starting from ethyl 2-cyanopropanoate and1-(2-methoxyethyl)urea. ⁷The requisite3-(3,4-dimethoxybenzyl)-1-ethyl-6-(4-hydroxyphenyl)-5-methylpyrimidine-2,4(1H,3H)-dionewas prepared following a procedure similar to that described for thepreparation of C30, starting from ethyl 2-cyanopropanoate and1-ethylurea. ⁸The requisite1-cyclopropyl-3-(3,4-dimethoxybenzyl)-6-(4-hydroxyphenyl)-5-methylpyrimidine-2,4(1H,3H)-dionewas prepared following a procedure similar to that described for thepreparation of C30, starting from ethyl 2-cyanopropanoate and1-cyclopropylurea. ⁹The requisite1-cyclopropyl-3-(3,4-dimethoxybenzyl)-5-ethyl-6-(4-hydroxyphenyl)pyrimidine-2,4(1H,3H)-dionewas prepared following a procedure similar to that described for thepreparation of C30, starting from ethyl 2-cyanobutanoate and1-cyclopropylurea. ¹⁰The requisite3-(3,4-dimethoxybenzyl)-1,5-diethyl-6-(4-hydroxyphenyl)pyrimidine-2,4(1H,3H)-dionewas prepared following a procedure similar to that described for thepreparation of C30, starting from ethyl 2-cyanobutanoate and1-ethylurea.

Example AA: Human D1 Receptor Binding Assay and Data

The affinity of the compounds described herein was determined bycompetition binding assays similar to those described in Ryman-Rasmussenet al., “Differential activation of adenylate cyclase and receptorinternalization by novel dopamine D1 receptor agonists”, MolecularPharmacology 68(4): 1039-1048 (2005). This radioligand binding assayused [³H]-SCH23390, a radiolabeled D1 ligand, to evaluate the ability ofa test compound to compete with the radioligand when binding to a D1receptor.

D1 binding assays were performed using over-expressing LTK human celllines. To determine basic assay parameters, ligand concentrations weredetermined from saturation binding studies where the K_(d) for[³H]-SCH23390 was found to be 1.3 nM. From tissue concentration curvestudies, the optimal amount of tissue was determined to be 1.75 mg/mLper 96 well plate using 0.5 nM of [³H]-SCH23390. These ligand and tissueconcentrations were used in time course studies to determine linearityand equilibrium conditions for binding. Binding was at equilibrium withthe specified amount of tissue in 30 minutes at 37° C. From theseparameters, K_(i) values were determined by homogenizing the specifiedamount of tissue for each species in 50 mM Tris (pH 7.4 at 4° C.)containing 2.0 mM MgCl₂ using a Polytron and spun in a centrifuge at40,000×g for 10 minutes. The pellet was resuspended in assay buffer [50mM Tris (pH 7.4@ RT) containing 4 mM MgSO₄ and 0.5 mM EDTA]. Incubationswere initiated by the addition of 200 μL of tissue to 96-well platescontaining test drugs (2.5 μL) and 0.5 nM [³H]-SCH23390 (50 μL) in afinal volume of 250 μL. Non-specific binding was determined byradioligand binding in the presence of a saturating concentration of(+)-Butaclamol (10 μM), a D1 antagonist. After a 30 minute incubationperiod at 37° C., assay samples were rapidly filtered throughUnifilter-96 GF/B PEI-coated filter plates and rinsed with 50 mM Trisbuffer (pH 7.4 at 4° C.). Membrane bound [³H]-SCH23390 levels weredetermined by liquid scintillation counting of the filterplates inEcolume. The IC₅₀ value (concentration at which 50% inhibition ofspecific binding occurs) was calculated by linear regression of theconcentration-response data in Microsoft Excel. K_(i) values werecalculated according to the Chena-Prusoff equation:

$K_{i} = \frac{{IC}_{50}}{1 + \left( {\lbrack L\rbrack/K_{d}} \right)}$

where [L]=concentration of free radioligand and K_(d)=dissociationconstant of radioligand for D1 receptor (1.3 nM for [³H]-SCH23390).

Example BB: D1 cAMP HTRF Assay and Data

The D1 cAMP (Cyclic Adenosine Monophosphate) HTRF (HomogeneousTime-Resolved Fluorescence) Assay used and described herein is acompetitive immunoassay between native cAMP produced by cells and cAMPlabeled with XL-665. This assay was used to determine the ability of atest compound to agonize (including partially agonize) D1. A Mabanti-cAMP labeled Cryptate visualizes the tracer. The maximum signal isachieved if the samples do not contain free cAMP due to the proximity ofdonor (Eu-cryptate) and acceptor (XL665) entities. The signal,therefore, is inversely proportional to the concentration of cAMP in thesample. A time-resolved and ratiometric measurement (em 665 nm/em 620nm) minimizes the interference with medium. cAMP HTRF assays arecommercially available, for example, from Cisbio Bioassays, IBA group.

Materials and Methods

Materials:

The cAMP Dynamic kit was obtained from Cisbio International (Cisbio62AM4PEJ). Multidrop Combi (Thermo Scientific) was used for assayadditions. An EnVision (PerkinElmer) reader was used to read HTRF.

Cell Culture:

A HEK293T/hD1#1 stable cell line was constructed internally (Pfizer AnnArbor). The cells were grown as adherent cells in NuncT₅₀₀ flasks inhigh glucose DMEM (Invitrogen 11995-065), 10% fetal bovine serumdialyzed (Invitrogen 26400-044), 1×MEM NEAA (Invitrogen 1140, 25 mMHEPES (Invitrogen 15630), 1× Pen/Strep (Invitrogen 15070-063) and 500μg/mL Genenticin (Invitrogen 10131-035) at 37° C. and 5% CO₂. At 72 or96 hours post-growth, cells were rinsed with DPBS, and 0.25%Trypsin-EDTA was added to dislodge the cells. Media was then added andcells were centrifuged and media removed. The cell pellets werere-suspended in Cell Culture Freezing Medium (Invitrogen 12648-056) at adensity of 4e7 cells/mL. One mL aliquots of the cells were made inCryo-vials and frozen at −80° C. for future use in the D1 HTRF assay.

D1 cAMP HTRF Assay Procedure:

Frozen cells were quickly thawed, re-suspended in 50 mL warm media andallowed to sit for 5 min prior to centrifugation (1000 rpm) at roomtemperature. Media was removed and cell pellet was re-suspended inPBS/0.5 μM IBMX generating 2e5 cells/mL. Using a Multidrop Combi, 5 μLcells/well was added to the assay plate (Greiner 784085), which alreadycontained 5 μL of a test compound. Compound controls [5 μM dopamine(final) and 0.5% DMSO (final)] were also included on every plate fordata analysis. Cells and compounds were incubated at room temperaturefor 30 min. Working solutions of cAMP-D2 and anti-cAMP-cryptate wereprepared according to Cisbio instructions. Using Multidrop, 5 μL cAMP-D2working solution was added to the assay plate containing the testcompound and cells. Using Multidrop, 5 μL anti-cAMP-cryptate workingsolutions was added to assay plate containing test compound, cells andcAMP-D2. The assay plate was incubated for 1 hour at room temperature.The assay plate was read on an EnVision plate reader using Cisbiorecommended settings. A cAMP standard curve was generated using cAMPstock solution provided in the Cisbio kit.

Data Analysis:

Data analysis was done using computer software. Percent effects werecalculated from the compound controls. Ratio EC₅₀ was determined usingthe raw ratio data from the EnVision reader. The cAMP standard curve wasused in an analysis program to determine cAMP concentrations from rawratio data. cAMP EC₅₀ was determined using the calculated cAMP data.

TABLE 2 Biological Data and Compound Name for Examples 1-23. Human D1Receptor Binding, K_(i) (nM); Geometric mean Example of 2-4determinations number (unless otherwise indicated) IUPAC Name 1 166^(a)4-[4-(4,6-dimethylpyrimidin-5-yl)-3- methylphenoxy]furo[2,3-d]pyrimidine2 374^(a) 4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]-1H-imidazo[4,5-c]pyridine 3 196^(a)6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one 4 127 (−)-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one 5 400^(a)(+)-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one 6  44.75-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one 7  30.7(+)-5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one 8  40.2(−)-5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one 9 142^(a)6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione 10  32.74,6-dimethyl-5-[2-methyl-4-([1,2]thiazolo[4,5-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one 11 912^(a)4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-imidazo[4,5-c]pyridine 12 367 5-[4-(1H-imidazo[4,5-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylpyrimidine-4-carbonitrile 13  70.35-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one 14 372^(a)5-[4-(furo[2,3-d]pyrimidin-4-yloxy)-2-methylphenyl]-4-methylpyridazin-3(2H)-one 15 280^(a)1,5-dimethyl-6-{4-[(3-methyl[1,2]oxazolo[4,5-c]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4(1H,3H)- dione 16 326^(a)4,6-dimethyl-5-{2-methyl-4-[(3- methyl[1,2]oxazolo[4,5-c]pyridin-4-yl)oxy]phenyl}pyridazin-3(2H)-one, trifluoroacetic acid salt 171730^(a)  1,5-dimethyl-6-{2-methyl-4-[(3-methyl[1,2]oxazolo[4,5-c]pyridin-4- yl)oxy]phenyl}pyrazin-2(1H)-one,trifluoroacetic acid salt 18 274^(a)5-ethyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1-methylpyrimidine-2,4(1H,3H)-dione 19 900^(a)6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-1-(2-methoxyethyl)-5-methylpyrimidine-2,4(1H,3H)-dione 20 179^(a)1-ethyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-5-methylpyrimidine-2,4(1H,3H)-dione 21 122^(a)1-cyclopropyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]-5-methylpyrimidine-2,4(1H,3H)-dione 22 142^(a)1-cyclopropyl-5-ethyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione 23 309^(a)1,5-diethyl-6-[4-(furo[2,3-d]pyrimidin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione ^(a)K_(i) value is from asingle determination

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appendant claims. Each reference (including all patents,patent applications, journal articles, books, and any otherpublications) cited in the present application is hereby incorporated byreference in its entirety.

What is claimed is:
 1. A method for treating a D1-mediated (orD1-associated) disorder in a mammal comprising administering to themammal a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is O, S,NR^(N), C(═O), CH(OH), or CH(OCH₃); Q¹ is an N-containing 5- to10-membered heteroaryl, an N-containing 4- to 12-memberedheterocycloalkyl, or phenyl, each optionally substituted with one R⁹ andfurther optionally substituted with 1, 2, 3, or 4 R¹⁰; X¹ is O, S, NH,N(C₁₋₄ alkyl), N(cyclopropyl), or N(—CH₂-cyclopropyl); X² is N or C-T²;X³ is N or C-T³; provided that when X¹ is O or S, then at least one ofX² and X³ is not N; X⁴ is N or C-T⁴; T¹ is H, —OH, halogen, —CN, oroptionally substituted C₁₋₂ alkyl; each of T², T³, and T⁴ isindependently selected from the group consisting of H, —OH, halogen,—CN, optionally substituted C₁₋₄ alkyl, optionally substituted C₃₋₄cycloalkyl, optionally substituted cyclopropylmethyl, and optionallysubstituted C₁₋₄ alkoxy; R^(N) is H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, or—C₁₋₂ alkyl-C₃₋₄ cycloalkyl, each of R¹ and R² is independently selectedfrom the group consisting of H, halogen, —CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and C₃₋₆ cycloalkyl, whereineach of said C₁₋₆ alkyl and C₃₋₆ cycloalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents each independently selected fromhalo, —OH, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy; each of R³ and R⁴ is independently selected from the groupconsisting of H, halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —NO₂, —CN,—SF₅, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, a 4- to 10-membered heterocycloalkyl,—N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸,—OC(═O)R⁸, —N(R⁷)(S(═O)₂R⁸), —S(═O)₂—N(R⁵)(R⁶), —SR⁸, and —OR⁸, whereineach of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and heterocycloalkyl isoptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl,—N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸), —C(═O)—OR⁸, —C(═O)H, —C(═O)R⁸,—C(═O)N(R⁵)(R⁶), —N(R⁷)(S(═O)₂R⁸), —S(═O)₂—N(R⁵)(R⁶), —SR⁸, and −OR⁸; orR¹ and R³ together with the two carbon atoms to which they are attachedform a fused N-containing 5- or 6-membered heteroaryl, a fusedN-containing 5- or 6-membered heterocycloalkyl, a fused 5- or 6-memberedcycloalkyl, or a fused benzene ring, each optionally substituted with 1,2, or 3 substituents each independently selected from the groupconsisting of halo, —CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ haloalkoxy; R⁵ is H, C₁₋₄ alkyl, C₁₋₄haloalkyl, or C₃₋₇ cycloalkyl; R⁶ is H or selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, a 4- to10-membered heterocycloalkyl, C₆₋₁₀ aryl, a 5- to 10-memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and (5- to10-membered heteroaryl)-C₁₋₄ alkyl-, wherein each of the selections fromthe group is optionally substituted with 1, 2, 3, or 4 substituents eachindependently selected from the group consisting of —OH, —NH₂, —NH(CH₃),—N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxylalkyl, —S—C₁₋₄alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;or R⁵ and R⁶ together with the N atom to which they are attached form a4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl,each optionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —OH, oxo,—C(═O)H, —C(═O)OH, —C(═O)—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂,—CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ hydroxylalkyl, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; R⁷ is selected from the group consisting of H, C₁₋₄alkyl, and C₃₋₇ cycloalkyl; R⁸ is selected from the group consisting ofC₁₋₆ alkyl, C₃₋₇ cycloalkyl, a 4- to 14-membered heterocycloalkyl, C₆₋₁₀aryl, a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-to 10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-,and (5- to 10-membered heteroaryl)-C₁₋₄ alkyl-, wherein each of theselections from the group is optionally substituted with 1, 2, or 3substituents each independently selected from the group consisting ofhalogen, —CF₃, —CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; each of R⁹ and R¹⁰ is independentlyselected from the group consisting of halogen, —OH, —CN, —SF₅, —NO₂,oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxylalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₄ alkyl-, (4- to 10-memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5- to10-membered heteroaryl)-C₁₋₄ alkyl-, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, —SR⁸, and—OR⁸, wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4-to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, and (5- to 10-memberedheteroaryl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, 3, or 4substituents each independently selected from the group consisting ofhalogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ hydroxylalkyl, C₁₋₄ alkoxy,—N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄ alkyl), C₆₋₁₀ aryloxy,[(C₆₋₁₀ aryl)-C₁₋₄ alkyloxy-optionally substituted with 1 or 2 C₁₋₄alkyl], oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄ alkyl, —C(═O)NH₂,—NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a 5- or 6-memberedheteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; or R⁹ and an adjacentR¹⁰ together with the two ring atoms on Q¹ to which they are attachedform a fused benzene ring or a fused 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, or 5 independently selectedR^(10a); and each R^(10a) is independently selected from the groupconsisting of halogen, —OH, —N(R⁵)(R⁶), —C(═O)OH, —C(═O)—C₁₋₄ alkyl,—C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, —CN, —SF₅, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ hydroxylalkyl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy, with theprovisos that (1) when X⁴ is N and X¹ is NH, N(C₁₋₄ alkyl),N(cyclopropyl), N(—CH₂-cyclopropyl), or S, then L¹ is other than NR^(N);(2) when X¹ is NH then X³ is other than N; (3) when X² is N, X³ is C-T³,X⁴ is C-T⁴, T³ is not H, and X¹ is NH, then L¹ is other than O orNR^(N); (4) when X² is C-T², X³ is C-T³, X⁴ is C-T⁴, then X¹ is otherthan S or O; (5) when L¹ is O, X³ is C-T³, and X⁴ is C-T⁴, then X¹ isother than NH; (6) when X¹ is NH, N(C₁₋₄ alkyl), N(cyclopropyl),N(—CH₂-cyclopropyl), or O, and X³ is N then L¹ is other than NR^(N); and(7) Q¹ is other than an optionally substituted benzo[d]thiazolyl or anoptionally substituted monocyclic 2-oxo-1H-pyridin-1-yl, and wherein thedisorder is selected from schizophrenia, schizotypal personalitydisorder, cognitive impairment, attention deficit hyperactivity disorder(ADHD), impulsivity, compulsive gambling, overeating, autism spectrumdisorder, mild cognitive impairment (MCI), age-related cognitivedecline, dementia, restless leg syndrome (RLS), Parkinson's disease,Huntington's chorea, anxiety, depression (e.g., age-related depression),major depressive disorder (MDD), treatment-resistant depression (TRD),bipolar disorder, chronic apathy, anhedonia, chronic fatigue,post-traumatic stress disorder, seasonal affective disorder, socialanxiety disorder, post-partum depression, serotonin syndrome, substanceabuse and drug dependence, drug abuse relapse, Tourette's syndrome,tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia,inattention, sexual dysfunction, migraine, systemic lupus erythematosus(SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity, diabetes,sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia,resistant edema, narcolepsy, hypertension, congestive heart failure,postoperative ocular hypotonia, sleep disorders, and pain.
 2. The methodof claim 1, wherein the compound of Formula I or a pharmaceuticallyacceptable salt thereof is a compound of Formula I-a, I-b, I-c, I-d, orI-e:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein: Q¹ is a moiety of

ring Q^(1a) is an N-containing 5- to 6-membered heteroaryl or anN-containing 5- to 6-membered heterocycloalkyl;

represents a single bond or double bond; each of Z¹ and Z² isindependently C or N; R⁹ is halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl, —CN, —N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or C₃₋₇cycloalkoxy, wherein each of the C₁₋₄ alkyl and C₃₋₇ cycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —N(R⁵)(R⁶),C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy; each R¹⁰ is independently selected from the group consistingof halogen, —OH, —CN, —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl,a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5-to 10-membered heteroaryl)-C₁₋₄ alkyl-, (5- to 10-memberedheteroaryl)-C₂₋₄ alkenyl-, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, and —OR⁸,wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4- to10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5- to 10-membered heteroaryl)-C₁₋₄alkyl-, and (5- to 10-membered heteroaryl)-C₂₋₄ alkenyl- is optionallysubstituted with 1, 2, 3, or 4 substituents each independently selectedfrom the group consisting of halogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄hydroxylalkyl, C₁₋₄ alkoxy, —N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄alkyl), C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)-C₁₄ alkyloxy-optionally substitutedwith 1 or 2 C₁₋₄ alkyl, oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄alkyl, —C(═O)NH₂, —NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a5- or 6-membered heteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; or R⁹and the adjacent R¹⁰ together with the two ring atoms on ring Q^(1a) towhich they are attached form a fused benzene ring or a fused 5- or6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(10a); each R^(10a) is independently selectedfrom the group consisting of halogen, —OH, —C(═O)OH, —C(═O)—C₁₋₄ alkyl,—C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄hydroxylalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy; and m is 0, 1, 2, 3, or
 4. 4. The method of claim 2,wherein: Q¹ is a moiety of

ring Q^(1a) is an N-containing 5- to 6-membered heteroaryl or anN-containing 5- to 6-membered heterocycloalkyl;

represents a single bond or double bond; each of Z¹ and Z² isindependently C or N; R⁹ is halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl, —CN, —N(R⁵)(R⁶), C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, or C₃₋₇cycloalkoxy, wherein each of the C₁₋₄ alkyl and C₃₋₇ cycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents eachindependently selected from the group consisting of halogen, —N(R⁵)(R⁶),C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy; each R¹⁰ is independently selected from the group consistingof halogen, —OH, —CN, —NO₂, oxo, thiono, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxylalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, a 4- to 10-membered heterocycloalkyl,a 5- to 10-membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4- to10-membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5-to 10-membered heteroaryl)-C₁₋₄ alkyl-, (5- to 10-memberedheteroaryl)-C₂₋₄ alkenyl-, —N(R⁵)(R⁶), —N(R⁷)(C(═O)R⁸),—S(═O)₂N(R⁵)(R⁶), —C(═O)—N(R⁵)(R⁶), —C(═O)—R⁸, —C(═O)—OR⁸, and —OR⁸,wherein each of said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, 4- to10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C₃₋₇cycloalkyl)-C₁₋₄ alkyl-, (4- to 10-membered heterocycloalkyl)-C₁₋₄alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-, (5- to 10-membered heteroaryl)-C₁₋₄alkyl-, and (5- to 10-membered heteroaryl)-C₂₋₄ alkenyl- is optionallysubstituted with 1, 2, 3, or 4 substituents each independently selectedfrom the group consisting of halogen, OH, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄hydroxylalkyl, C₁₋₄ alkoxy, —N(R⁵)(R⁶), —S—(C₁₋₄ alkyl), —S(═O)₂—(C₁₋₄alkyl), C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)-C₁₋₄ alkyloxy-optionally substitutedwith 1 or 2 C₁₋₄ alkyl, oxo, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)O—C₁₋₄alkyl, —C(═O)NH₂, —NHC(═O)H, —NHC(═O)—(C₁₋₄ alkyl), C₃₋₇ cycloalkyl, a5- or 6-membered heteroaryl, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; or R⁹and the adjacent R¹⁰ together with the two ring atoms on ring Q^(1a) towhich they are attached form a fused benzene ring or a fused 5- or6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5independently selected R^(10a); each R^(10a) is independently selectedfrom the group consisting of halogen, —OH, —C(═O)OH, —C(═O)—C₁₋₄ alkyl,—C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄hydroxylalkyl, (C₁₋₂ alkoxy)-C₁₋₄ alkyl-, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy; and m is 0, 1, 2, 3, or 4.